CELL SCIENCE AT A GLANCE

Emerging functions of the Fanconi anemia pathway at a glanceRhea Sumpter, Jr1,*,‡ and Beth Levine1,2

ABSTRACTFanconi anemia (FA) is a rare disease, in which homozygous orcompound heterozygous inactivating mutations in any of 21 geneslead to genomic instability, early-onset bone marrow failure andincreased cancer risk. The FA pathway is essential for DNA damageresponse (DDR) to DNA interstrand crosslinks. However, proteins ofthe FA pathway have additional cytoprotective functions that may beindependent of DDR. We have shown that many FA proteinsparticipate in the selective autophagy pathway that is required forthe destruction of unwanted intracellular constituents. In this CellScience at a Glance and the accompanying poster, we briefly reviewthe role of the FA pathway in DDR and recent findings that link

proteins of the FA pathway to selective autophagy of viruses andmitochondria. Finally, we discuss how perturbations in FA protein-mediated selective autophagy may contribute to inflammatory as wellas genotoxic stress.

KEY WORDS: Selective autophagy, Fanconi anemia, Mitophagy,Inflammasome, Virophagy, DNA damage response

IntroductionFanconi anemia (FA), first described by Guido Fanconi in 1927, is arare and potentially devastating disease associated with inactivatinghomozygous or compound heterozygous mutations − except in thecase of the gene for Fanconi anemia complementation group(FANC) B (FANCB), which is X chromosome-linked− in any of 21FA genes (Garaycoechea and Patel, 2014). Affected patients sufferfrom bone marrow failure (with a 90% prevalence in the first decadeof life), increased cancer susceptibility − particularly to acutemyelogenous leukemia and squamous cell carcinomas of the upperdigestive and urogenital tracts, and premature gonadal failure.Although some patients are phenotypically normal, congenital

1Center for Autophagy Research, Department of Internal Medicine, University ofTexas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390,USA. 2Howard Hughes Medical Institute, University of Texas Southwestern MedicalCenter, Dallas, TX 75390, USA.*Present address: Department of Immunology, St. Jude Children’s ResearchHospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.

‡Author for correspondence (rhea.sumpter@stjude.org)

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defects are often associated with FA, e.g. skeletal and skinabnormalities (Neveling et al., 2009). Although FA is a raredisease, inherited and somatic mutations or epigenetic silencing ofFA genes are also found in many cancers. These include breast andovarian cancers in patients with mutations of the inherited breastcancer susceptibility gene 1 (BRCA1), or breast cancersusceptibility gene 2 (BRCA2), as well as pancreatic, brain andother cancers that are associated with a loss-of-function of FA genes(D’Andrea, 2010; Mamrak et al., 2016) (see Box 1). In this CellScience at a Glance article and accompanying poster, wewill brieflyreview the role of the FA pathway in DNA damage response (DDR)and then explore a recently described function of FA proteins inselective autophagy and its implications for our understanding of thepathophysiology of FA.

Role of the FA pathway in DDR to of interstrand crosslinksThe FA pathway is required for the DDR to interstrand crosslinks(ICLs), highly toxic lesions in which adjacent bases on oppositeDNA strands are covalently linked (Mamrak et al., 2016;Michl et al., 2016). It has been estimated that each human cell hasto repair ∼10 ICLs/day (Grillari et al., 2007) and that as few as 20-40 unresolved ICL lesions can lead to cell death (Clauson et al.,2013). ICLs are generated during treatment with certainchemotherapeutic agents (e.g. nitrogen mustards, Mitomycin C,or Cisplatin) (Lopez-Martinez et al., 2016). However, even inthe absence of exogenous insults, endogenous sources, such asreactive oxygen species (ROS) and their peroxidated intermediates,as well as reactive aldehydes, induce- ICLs (Clauson et al.,2013; Lopez-Martinez et al., 2016), although their relativecontributions to the burden of ICLs in a given cell population are

difficult to quantify. Unrepaired ICLs, ultimately, lead to DNAbreakage and chromosomal rearrangements, and promote thedevelopment and/or progression of cancer (see below) (Ceccaldiet al., 2016).

Detection of ICLs by DDR surveillance proteins results in theactivation of an eight-member FA core complex (consisting ofFANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCLand FANCM) that directs the E3 ubiquitin ligase activity of FANCLto monoubiquitylate and thereby activate the DNA-bindingheterocomplex between Fanconi anemia group D2 protein(FANCD2) and FANCI (see poster). The active FANCD2−FANCI complex, in turn, orchestrates the concerted downstreamactions of the FA pathway and accessory proteins to resolve the ICLlesion (Boisvert and Howlett, 2014; Kim and D’Andrea, 2012;Mamrak et al., 2016; Renaudin et al., 2016) (see poster). Thus, FAproteins are crucial factors in the maintenance of genomic integrity;in fact, the FA pathway is the only known mechanism of repair forICLs that, if left unrepaired, promote genotoxic stress, genomicinstability and tumorigenesis.

Other nuclear functions of the FA pathway in genomemaintenance and DDRIn addition to its canonical role in ICL repair, accumulatingevidence indicates that subsets of FA proteins also participate inadditional pathways that are crucial to maintain genomic integrity(see poster) (reviewed in detail by Ceccaldi et al., 2016). Forexample, heterodimers of ubiquitylated FANCD2 and FANCI (and,additionally, the FA core complex and accessory proteins) localizeto stalled replication forks (Lossaint et al., 2013), where they protectnascent (single-stranded) DNA from degradation by nucleases(Schlacher et al., 2011, 2012) and suppress inappropriate new originfiring and entry into mitosis (Chaudhury et al., 2013; Chen et al.,2015). These functions prevent a destabilization or collapse of thereplication fork and, thus, any resulting genomic instability(Ceccaldi et al., 2016). Members of the FA pathway are alsorequired for the suppression of non-homologous end-joining(Renaud et al., 2016), the correct segregation of chromosomesduring cytokinesis (Chan et al., 2009; Naim and Rosselli, 2009), aswell as for numerous other forms of non-ICL-directed DDR,including nucleotide excision repair (Kelsall et al., 2012),translesion synthesis (Haynes et al., 2015), homologousrecombination (Haynes et al., 2015) and alternative end joining(Nguyen et al., 2014). Thus, FA pathway proteins participate indiverse non-canonical (i.e. non-ICL repair) roles in concert withother pathways that are involved in genomic stability and DDR toameliorate many forms of genotoxic stress.

Clues to aDDR-independent role for FANCC in cytoprotectionAlthough hypersensitivity to DNA damage is the best knownphenotype of cells that are deficient in FA-gene function (Ceccaldiet al., 2016), it has long been appreciated that, at least some,genes of the FA pathway play additional cytoprotective roles, suchas protection from cell death induced by ROS (Schindler andHoehn, 1988), proinflammatory cytokines (Haneline et al., 1998;Whitney et al., 1996) or growth factor withdrawal (Cumminget al., 1996). Previous studies have offered some insight intopossible mechanisms underlying the cytoprotective effects ofthe FA protein FANCC. For example, FANCC-mediatedprotection against proinflammatory cytokine-induced cell deathis correlated with its biochemical interactions with signaltransducer and activator of transcription 1 (STAT1) (Pang et al.,2000), protein kinase R (PKR; officially known as EIF2AK2) (Pang

Box 1. FA proteins and proteins associated with FAfeaturing in this articleOfficial protein names are given in boldBRAC1: breast cancer susceptibility gene 1 (also known as FANCS)BRAC2: breast cancer susceptibility gene 2 (also known as FACD,FANCD1)BRIP1: BRCA1 interacting protein C-terminal helicase 1 (also known asFANCJ)ERCC4: excision repair 4, endonuclease catalytic subunit (also knownas FANCQ)FAAP20: FA core complex associated protein 20FAN1: FANCD2 and FANCI-associated nuclease 1FANCA: Fanconi anemia complementation group (FA comp group)A proteinFANCB: FA comp group B proteinFANCC: FA comp group C proteinFANCD2: FA comp group D2 protein (also known as FACD, FANCD)FANCE: FA comp groupEFANCF: FA comp group FFANCG: FA comp group GFANCI: FA comp group I proteinFANCL: FA comp group L protein (also known as E3 ubiquitin-proteinligase FANCL)FANCM: FA comp group M proteinMAD2L2: mitotic arrest-deficient-2-like 2 (also known as REV7, FANCV)PALB2: partner and localizer of BRCA2 (also known as FANCN)RAD51: RAD51 recombinase (also known as FANCR)RAD51C: RAD51 paralog C (also known as FANCO)SLX4: structure-specific endonuclease subunit SLX4 (also known asFANCP)UBE2T: ubiquitin-conjugating enzyme 2 T (also known as FANCT)XRCC2: X-ray repair cross-complementing 2 (also known as FANCU)

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et al., 2002) and stress-inducible heat shock protein 70(HSPA1A) (Pang et al., 2002, 2001b). FANCC-mediatedprotection against growth factor withdrawal-induced cell death isassociated with its interaction and activation of the xenobiotic- andROS-detoxifying enzyme glutathione S-transferase P1 (GSTP1)(Cumming et al., 2001).Some of the earliest work on FANCC indicated that at least some

of its cytoprotective roles might be independent of its role in DDR.For example, already in 1996, Yamashita et al. demonstrated thatcells of FA patients that endogenously express the naturallyoccurring FANCC mutant c.67delG (which results in the use ofan alternative start codon and the deletion of 54 N-terminal aminoacids) were indistinguishable from FA patient cells that harbor a nullmutation in FANCC with respect to their hypersensitivity tomitomycin C (MMC)-induced DNA damage (Yamashita et al.,1996). However, patients that carry the c.67delG mutant have amilder clinical course than patients with null mutations in FANCC(i.e. mutations that abrogate both its DDR and cytoprotective roles),suggesting that FANCC has other disease-modulating functions thatare independent of its role in DDR (Neveling et al., 2009). Indeed,in a previous study, the FANCC c.67delG mutant was shown torescue interferon-γ (IFNγ)-induced STAT1 activation, which iscorrelated with resistance to cell death induced by IFNγ and/ortumor necrosis factor-α (TNFα), to the same extent as wild-typeFANCC (Pang et al., 2001a). Taken together, these in vitro resultsand clinical observations hint at the existence of a clinicallyimportant additional function or functions of FANCC beyond itsrole in DDR.

Identification of FA proteins as putative selective autophagyfactorsAutophagy is a phylogenetically conserved cellular housekeepingpathway that plays pleiotropic roles in cellular and organismalhomeostasis (Levine and Kroemer, 2008). In contrast to general(e.g. starvation-induced) autophagy, which is thought to benonspecific, a specialized form of autophagy that has been termedselective autophagy, specifically targets unwanted cytoplasmiccontents (e.g. viruses, intracellular bacteria, damaged mitochondriaand endoplasmic reticulum, lipid droplets, peroxisomes) forengulfment by double-membraned vesicles (the so-calledautophagosomes) and then delivered to lysosomes for destruction(Khaminets et al., 2016). Although our understanding of themechanism(s) of selective autophagy has progressed significantly inrecent years, much remains to be learned about this process before itcan be harnessed for clinical use, for instance, to treat infectiousdiseases, cancer and conditions related to aging.To this end, we performed a high-content, image-based, genome-

wide screen to identify host factors involved the selective autophagyof Sindbis virus (virophagy) (Orvedahl et al., 2011). This screenidentified genes that blocked the colocalization of a red fluorescentSindbis virus capsid protein with microtubule-associated protein 1light chain 3 alpha (MAP1LC3A, also known as LC3) conjugated togreen fluorescent protein (GFP-LC3), a marker of autophagosomes.To our surprise, three FA genes, FANCC, FANCF and FANCL that,like the other FA genes, had no known association with autophagy,were confirmed positives in the virophagy screen. We also found ahigh degree of overlap between the positives from the virophagyscreen and the genes that are required for another type of selectiveautophagy – Parkin-mediated autophagy of damaged mitochondria(a form of mitophagy) – suggesting a conservation of cellular factorsrequired for the selective autophagy of seemingly unrelatedcytoplasmic cargoes.

FANCC is required for virophagyWe first confirmed that FANCC is not required for non-selectivestarvation-induced autophagy but is required for Sindbis virophagyin murine embryonic fibroblasts (MEFs) because the colocalizationof mCherry-labeled Sindbis virus capsids and autophagosomes isreduced in Fancc−/− MEFs (Sumpter et al., 2016). We also foundthat virophagy of a herpes simplex virus type 1 (HSV-1) mutant thatlacks a 20 amino acid region of the infected cell protein 34.5(ICP34.5) neurovirulence gene product − rendering it incapable ofbinding to the essential autophagy protein Beclin 1 and inhibitingautophagy− is impaired in Fancc−/−MEFs. Ultrastructural analysisof the cytoplasm of wild-type MEFs revealed that HSV-1nucleocapsids are primarily located within autolysosomes and inthe process of being degraded. In contrast, in Fancc−/− MEFs, intactHSV-1 nucleocapsids and enveloped virions can be found free in thecytoplasm, suggesting a failure of their targeting to autophagosomes/autolysosomes (see poster). Similar to other previously identifiedvirophagy factors, such as sequestosome 1 (SQSTM1) (Orvedahlet al., 2010) and SMAD-specific E3 ubiquitin protein ligase 1(SMURF1) (Orvedahl et al., 2011), FANCC (as well as FANCA)interacted biochemically with the Sindbis virus capsid protein.Additionally, both FANCC and Sindbis virus capsid protein can beimmunoprecipiated within LC3-positive membrane structures, whichare indicative of autophagosomes.

Importantly, Fancc−/− mice are more susceptible to death afterintracerebral inoculation with both the neuronotropic RNA virus(Sindbis) and the neuronotropic DNA virus (HSV-1) (Sumpteret al., 2016). This increased susceptibility to lethal CNS infection isassociated with increased neuronal cell death (as measured byTUNEL staining; see poster) and increased viral antigen loads, butnot with raised levels of infectious virus titers. These phenotypes inmice with deletion of a selective autophagy factor (FANCC) areconsistent with those observed in previous studies of mice withneuronal deficiency of Atg5 − a core component of the autophagymachinery (Orvedahl et al., 2010; Yordy et al., 2012). These resultssuggest that the autophagy pathway exerts its pro-survival roleduring viral infections of the CNS by removing excess viral proteinproducts and preventing cell death due to proteotoxicity, i.e. damageof cellular functions due to protein misfolding.

Taken together, the in vitro and in vivo studies with Sindbis virusand HSV-1 (see poster) indicate that FANCC is an adaptor proteinduring virophagy that functions in antiviral host defense in the CNS(Sumpter et al., 2016). The precise mechanism by which FANCCand, potentially, additional FA proteins function to deliver viralcargoes for autophagic destruction remains to be elucidated, as dothe precise mechanisms by which FANCC protects mice in vivoagainst lethal neuronotropic viral disease.

FANCC is required for mitophagy in a DDR-independentmannerWhile by definition selective autophagy is associated with exquisitecargo selectivity, there is also extensive evidence for sharedmechanisms that are involved in the selective targeting of diverseintracellular cargoes (Khaminets et al., 2016). For example, the E3ligase Parkin plays an important role in both the removal ofdamaged mitochondria (mitophagy) (Pickrell and Youle, 2015) andthe autophagic targeting of the intracellular bacteriumMycobacterium tuberculosis (Manzanillo et al., 2013). Moreover,as noted above, there is extensive overlap between genes (includingFANCC, FANCF and FANCL) that are required for selectivevirophagy and mitophagy − another form of selective autophagy(Orvedahl et al., 2011).

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The concept that FA proteins can function in mitophagy isattractive as a potential mechanism that contributes to thecytoprotective functions of FANCC (discussed above) and apreviously described role for FA proteins in mitochondrial qualitycontrol. Kumari et al. found that FA-deficient cells have a number ofmitochondrial defects, including elevated levels of mitochondrialROS, decreased mitochondrial membrane potential, decreased ATPproduction, impaired oxygen uptake and abnormal mitochondrialmorphology (Kumari et al., 2014), although the molecular basis ofthe latter phenotype has not been described yet.We confirmed a role for FANCC inmitophagy by using CRISPR/

Cas9-mediated deletion in HeLa cells (see poster), FANCC mutantfibroblasts of FA patients and bone marrow-derived macrophages(BMDMs) from Fancc-deficient mice (Sumpter et al., 2016).Furthermore, we observed the accumulation of damagedmitochondria in post-mitotic tissues (i.e. brain and heart) of agedFancc−/− mice (see poster) (Sumpter et al., 2016), a finding that isconsistent with a defect in mitochondrial quality control in vivo. Wecould also show that FANCC (as well as FANCA) interactedbiochemically with the E3 ubiquitin ligase Parkin and translocatedto mitochondria (see poster) in a Parkin- andmitochondrial damage-dependent manner (Sumpter et al., 2016).The role of FANCC in Parkin-mediated mitophagy appears to be

genetically distinct from its role in DDR. Specifically, the c.67delGFANCC mutant, which − as mentioned above − is not functional inDDR but fully functional in protecting cells against cytokine-induced death, can completely restore Parkin-mediated mitophagyin FANCC knockout cells (Sumpter et al., 2016). Although theseresults strongly suggest that the DDR function of FANCC isdispensable for Parkin-mediated mitophagy, further studies arerequired to rule out other potential nuclear functions of FANCC inmitophagy.

Defective FANCC-mediated mitophagy and suppression ofmtROS results in aberrant inflammasome signalingDamaged mitochondria produce mitochondrial reactive oxygenspecies (mtROS) that activate the NACHT, LRR and PYD domain-containing protein 3 (NLRP3) inflammasome pathway, resulting inthe caspase-1-mediated cleavage of pro-IL-1β (pro-interleukin-1β)followed by secretion of the potent proinflammatory cytokineinterleukin-1β (IL-1β) (Zhou et al., 2011), and mitophagydownregulates inflammasome signaling by removing mtROS(Zhong et al., 2016) (see poster). Given the emerginginterrelationships between mitophagy, mtROS and inflammasomeactivation, coupled with previous reports that link FANCCdeficiency and increased mitochondrial ROS production (Kumariet al., 2014) or hyperactivation of inflammasome signaling (Garbatiet al., 2013), we sought to determine whether a failure to clearmtROS-producing damaged mitochondria is responsible forenhanced inflammasome activation in FANCC-deficient cells.Indeed, primary BMDMs from Fancc−/− mice, primed with thepathogen-associated molecular pattern (PAMP) lipopolysaccharide(a component of the cell wall of Gram-negative bacteria) and thentreated with extracellular ATP (to mimic the ‘danger’ signal fromnearby dying cells) (de Zoete et al., 2014), results in increasedmtROS generation, hypersecretion of IL-1β, and generation of moreand larger apotosis-associated speck-like protein containing acontaining a caspase recruitment domain (PYCARD, hereafterreferred to as ASC) specks (i.e. markers of inflammasome assembly,overlying damaged mitochondria; see poster) (Sumpter, 2016). Inagreement, addition of MitoTEMPO, a mtROS-specific free radicalscavenger, dramatically reduces IL-1β secretion and ASC speck

formation, which is consistent with a model in which failure ofFANCC-mediated mitophagy during inflammasome activationresults in mtROS-driven hyperactivation of the inflammasomeand associated hypersecretion of IL-1β (see poster).

Additional FA proteins are required for mitophagyThe role for FA proteins in Parkin-mediated mitophagy seems toextend to multiple family members. At least in siRNA knockdownstudies, the core complex proteins FANCF, FANCL and FANCA(the most commonly mutated protein in FA patients) are required,along with FANCD2, BRCA1 and BRCA2, which have no knowndirect functions outside the nucleus (see poster) (Sumpter et al.,2016). Moreover, another group recently found that cells frompatients that carry FANCA (or FANCC) mutations have impairedlevels of both basal and mitochondrial uncoupling agent-inducedmitophagy (Shyamsundar et al., 2016).

Currently, it is impossible to conclude whether the differentFA proteins function directly inmitophagyor indirectly, i.e. as a resultof other defined cellular functions, including the nuclear rolesdiscussed above. Although it conceptually more straightforward topostulate direct roles for FA proteins that are already known to havecytoplasmic functions, the possibility of direct roles for other FAproteins without any known cytoplasmic functions warrants furtherinvestigation. A mitochondrial localization of some of these proteinshas been described, although, except for a role in mitophagy, nomitochondrial function is currently known. For example, FANCD2that is not monoubiquitylated (and, therefore, not targeted by the FAcore complex) is constitutively present in immunoprecipitatedmitochondria (Sumpter et al., 2016), and a fraction of BRCA1 islocated at the mitochondrial matrix (Coene et al., 2005).

A general role for DDR pathways in mitochondrial qualitycontrol and mitophagy?In recent years, evidence has mounted that defects in multiple non-FA DDR pathways result in defective mitophagy, leading toaccumulation of damaged mitochondria and concomitant increasedintracellular oxidative stress (Drake et al., 2017). These defectsinclude mutations in the ataxia-telangiectasia (A-T) double-strandbreak repair pathway (Valentin-Vega et al., 2012), the Cockaynesyndrome B transcription-coupled repair pathway (Scheibye-Knudsen et al., 2012) and the xeroderma pigmentosum group Anucleotide excision repair pathway (Fang et al., 2014). Interestingly,the A-T serine/threonine kinase (ATM) has also been shown to berequired for pexophagy, the removal of peroxisomes (which are alsoa source of intracellular ROS) by selective autophagy (Zhang et al.,2015). This suggests that, like FANCC, ATM is also required for theremoval of diverse substrates by the selective autophagy pathway.As with FA proteins, more studies are needed to determine theprecise molecular mechanisms by which other non-FA, DDRpathway proteins function in selective autophagy.

Physiological consequences of defects in mitophagyA causal connection between mitophagy and tumor suppression isstrongly supported by the observations that mitophagy-associatedproteins, including the E3 ubiquitin-protein ligase parkin (PARK2),Bcl-2/adenovirus E1B 19-kDa-interacting protein 3 (BNIP3) andBcl-2/adenovirus E1B 19-kDa-interacting protein 3-like (BNIP3L)have been linked with cancer (Chourasia et al., 2015). Pathogenicalterations in mitochondrial homeostasis are thought to contribute totumorigenesis through a variety of mechanisms. These includechanges in mitochondrial metabolic pathways to support tumor cellmetabolism (metabolic reprogramming), as well as pro-tumor

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changes in cell signaling due to oxidative post-translational proteinmodifications (Vyas et al., 2016). Mitochondria-derived ROS alsodirectly or indirectly oxidize cellular macromolecules (e.g. proteins,lipids, DNA), ultimately leading to increased genotoxic stress(Drake et al., 2017; Vyas et al., 2016). Thus, a potential role formitophagy in the pathogenesis of cancers in FA and other DDR-associated diseases associated with the accumulation of damagedmitochondria warrants further exploration.Aberrant IL-1β signaling, which is another consequence of

defective mitophagy (Zhou et al., 2011), has been implicated in awide range of pathophysiologies, including autoinflammatorydiseases (Zhong et al., 2016), cancer (Zitvogel et al., 2012),metabolic disorders (de Zoete et al., 2014) and senescence (Salamaet al., 2014). Drugs targeting the inflammasome pathway are alreadyused to treat some of these diseases (Shao et al., 2015). A crucialunanswered question is to what extent aberrant inflammasomeactivation, in addition to genotoxic stress, contributes to bonemarrow failure, cancer susceptibility and developmentalabnormalities − all of which are observed in patients that carrymutations of FANCC and other FA genes (Auerbach, 2009;Ceccaldi et al., 2016; Mamrak et al., 2016; Neveling et al., 2009).

ConclusionsThe FA pathway is crucial not only in DDR of ICLs but it also hasemerging roles in other nuclear functions (stabilization ofreplication forks, cytokinesis and other types of DNA repair), aswell as in the cytoplasmic process of selective autophagy. Althoughthere are many open questions regarding the mechanism of action ofFA proteins in their ‘non-canonical’ roles, the exciting emerginglinks between the FA pathway and selective autophagy mightprovide a roadmap to new and unexpected therapeutic targets inorder to treat FA and diseases associated with FA gene mutations.An intriguing question iswhy the FApathwaywould be involved in

selective autophagy in addition to its role in DDR. We speculate thispathway is involved because ROS can inflict the type of DNA lesion(ICL) the FA pathway is required to repair; moreover, it acts at twocrucial stages to protect the cell against genotoxic stress. By helpingto remove the main endogenous source of ROS (mtROS fromdamaged mitochondria), members of the FA pathway minimize thegeneration of nuclear ICLs. As well as deficiencies in the direct FADNA repair pathway, the failure to suppress extensive genotoxicstress emanating from the cytoplasm by FA proteins might beimportant in the pathophysiologies associated with FA, such ascancer and accelerated aging (Brosh et al., 2017; Drake et al., 2017).More broadly, it is possible that other types of DNA damage linkedto ROS are also modulated by mitophagy, thus providing a commonselective pressure for different DNA damage pathways to functiontogether in selective autophagy (Drake et al., 2017).

AcknowledgementsWe are grateful to Angela Diehl for assistance with the graphic design andillustrations of the poster.

Competing interestsThe authors declare no competing or financial interests.

FundingWork in B.L.’s laboratory was supported by the National Institutes of Health (grantnumbers: K08 AI099150 to R.S., U19 AI109725 to B.L., RO1CA109618 to B.L.), theBurroughs Wellcome Fund (Career Award for Medical Scientists to R.S.), theUniversity of Texas Southwestern Medical Center President’s Research Council(Distinguished Researcher Award to R.S.), and the Cancer Prevention andResearch Institute of Texas (grant number: RP120718 to B.L.). Deposited in PMCfor release after 12 months.

Cell science at a glanceA high-resolution version of the poster and individual poster panels are available fordownloading at http://jcs.biologists.org/lookup/doi/10.1242/jcs.204909.supplemental

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