FANCM and FAAP24 Function in ATR-Mediated Checkpoint Signaling Independently of the Fanconi Anemia Core Complex

Collis, Spencer J.; Ciccia, Alberto; Deans, Andrew J.; Hořejšı́, Zuzana; Martin, Julie S.; Maslen, Sarah; Skehel, J. Mark; Elledge, Stephen J.; West, Stephen C.; Boulton, Simon J.

doi:10.1016/j.molcel.2008.10.014

Cited by 184 publications

(221 citation statements)

References 47 publications

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“…In agreement with our data, Pichierri and Rosselli (2) demonstrated that in human cells, a DNA cross-link-induced S phase checkpoint is branched downstream of ATR, with one branch depending on Chk1 and the other depending on the FA proteins, indicating that chk1 and FA pathway act independently of each other. On the other hand, a recent study by Collis et al (44) showed that HeLa cells lacking FANCM exhibit strongly reduced levels of Chk1 phosphorylation at Ser 317 in response to replication fork stalling. In human cells, Chk1 phosphorylation by ATR occurs at two sites, Ser 317 and Ser 345 , in response to replication fork stalling.…”

Section: Discussionmentioning

confidence: 94%

The Fanconi Anemia Protein FANCM Is Controlled by FANCD2 and the ATR/ATM Pathways

Sobeck¹,

Stone

Landais

et al. 2009

Journal of Biological Chemistry

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In addition to monoubiquitination by the FA core complex, FANCD2 and FANCI are phosphorylated by the two major cell cycle checkpoint kinases, ATM (ataxia telangiectasia mutated) and ATR (ATM and Rad3-related),y in response to DNA damage (2-6). ATM-dependent phosphorylation of FANCD2 occurs following ionizing irradiation and is required for activation of the ionizing irradiation-induced intra-S phase checkpoint (4). ATR-dependent phosphorylation of FANCD2 is triggered by various types of DNA damage, including replication stress, and is required for the interstrand cross-link-induced intra-S phase checkpoint response (2, 3). Moreover, phosphorylation by ATR is required for efficient FANCD2 monoubiquitination in response to DNA damage, suggesting that the FA pathway might participate in ATR-dependent coordination of the S phase of the cell cycle (3, 7).The recent identification of a highly conserved FA core complex member, FANCM (8, 9), indicates a direct role of FA pathway proteins in repair steps at sites of DNA damage. FANCM is a homolog of the archaebacterial Hef protein (helicase-associated endonuclease for fork-structured DNA) and contains two DNA processing domains: a DEAH box helicase domain and an XPF/ERCC4-like endonuclease domain. FANCM has ATP-dependent DNA translocase activity and can dissociate DNA triple helices in vitro (8). Moreover, FANCM binds Holliday junctions and DNA replication fork structures in vitro and promotes ATP-dependent branch point migration, suggesting that FANCM might be involved in DNA processing at stalled replication forks (10,11). In human cells, FANCM localizes to chromatin and is required for chromatin recruitment of other FA core complex proteins (8,12). FANCM is phosphorylated during both the M and S phases and in response to DNA-damaging agents (8,12,13). Interestingly, DNA damage-induced phosphorylation of FANCM is independent of the FA core complex (8), suggesting that FANCM is controlled by other, as yet unknown upstream components of the DNA damage response. Here, we used cell-free Xenopus egg extracts to investigate the role of FANCM during replication and in the DNA damage response. We show that Xenopus FANCM (xFANCM) binds chromatin in a replication-dependent manner and is phosphorylated during unperturbed replication as well as in response to various DNA damage structures. Both chromatin recruitment and phosphorylation of xFANCM are partially controlled by xFANCD2, suggesting feedback signaling from xFANCD2 to the upstream xFA core complex via regulation of xFANCM. In addition, chromatin recruitment during unperturbed replication and activation of xFANCM in response to DNA damage are controlled by the xATR and xATM cell cycle kinases.

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Section: Discussionmentioning

confidence: 94%

The Fanconi Anemia Protein FANCM Is Controlled by FANCD2 and the ATR/ATM Pathways

Sobeck¹,

Stone

Landais

et al. 2009

Journal of Biological Chemistry

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“…It forms a heterodimeric complex with FAAP24 (FA-associated protein 24 kDa), and the complex resembles an XPF-ERCC1 structure-specific endonuclease pair . The FANCM-FAAP24 complex plays multiple roles in pathway activation by recognizing the DNA lesion and recruiting the FA core complex, stabilizing the stalled replication fork, and initiating ATR (ataxia-telangiectasia and Rad3-related)-mediated checkpoint signaling (Ciccia et al 2007;Collis et al 2008;Schwab et al 2010). Histone fold protein 1 (MHF1) and MHF2 maintain the stable association of FANCM with chromatin and augment efficient pathway activation (Singh et al 2010;Yan et al 2010).…”

Section: The Fanconi Anemia (Fa) Pathwaymentioning

confidence: 99%

Regulation of DNA cross-link repair by the Fanconi anemia/BRCA pathway

Kim¹,

D’Andrea²

2012

Genes Dev.

445

499

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The maintenance of genome stability is critical for survival, and its failure is often associated with tumorigenesis. The Fanconi anemia (FA) pathway is essential for the repair of DNA interstrand cross-links (ICLs), and a germline defect in the pathway results in FA, a cancer predisposition syndrome driven by genome instability. Central to this pathway is the monoubiquitination of FANCD2, which coordinates multiple DNA repair activities required for the resolution of ICLs. Recent studies have demonstrated how the FA pathway coordinates three critical DNA repair processes, including nucleolytic incision, translesion DNA synthesis (TLS), and homologous recombination (HR). Here, we review recent advances in our understanding of the downstream ICL repair steps initiated by ubiquitin-mediated FA pathway activation.

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“…41,42 In S. pombe, Fml1 is shown to play a role in promoting HR at stalled replication forks. 43 Importantly, our present studies identified NER and HR as the major DNA repair mechanisms involved in acetaldehyde response.…”

Section: Ner Acts Downstream Of Fml1mentioning

confidence: 99%

Genetic controls of DNA damage avoidance in response to acetaldehyde in fission yeast

et al. 2016

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Acetaldehyde, a primary metabolite of alcohol, forms DNA adducts and disrupts the DNA replication process, causing genomic instability, a hallmark of cancer. Indeed, chronic alcohol consumption accounts for approximately 3.6% of all cancers worldwide. However, how the adducts are prevented and repaired after acetaldehyde exposure is not well understood. In this report, we used the fission yeast Schizosaccharomyces pombe as a model organism to comprehensively understand the genetic controls of DNA damage avoidance in response to acetaldehyde. We demonstrate that Atd1 functions as a major acetaldehyde detoxification enzyme that prevents accumulation of Rad52-DNA repair foci, while Atd2 and Atd3 have minor roles in acetaldehyde detoxification. We found that acetaldehyde causes DNA damage at the replication fork and activates the cell cycle checkpoint to coordinate cell cycle arrest with DNA repair. Our investigation suggests that acetaldehyde-mediated DNA adducts include interstrand-crosslinks and DNA-protein crosslinks. We also demonstrate that acetaldehyde activates multiple DNA repair pathways. Nucleotide excision repair and homologous recombination, which are both epistatically linked to the Fanconi anemia pathway, have major roles in acetaldehyde tolerance, while base excision repair and translesion synthesis also contribute to the prevention of acetaldehyde-dependent genomic instability. We also show the involvement of Wss1-related metalloproteases, Wss1 and Wss2, in acetaldehyde tolerance. These results indicate that acetaldehyde causes cellular stresses that require cells to coordinate multiple cellular processes in order to prevent genomic instability. Considering that acetaldehyde is a human carcinogen, our genetic studies serve as a guiding investigation into the mechanisms of acetaldehyde-dependent genomic instability and carcinogenesis.

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FANCM and FAAP24 Function in ATR-Mediated Checkpoint Signaling Independently of the Fanconi Anemia Core Complex

Cited by 184 publications

References 47 publications

The Fanconi Anemia Protein FANCM Is Controlled by FANCD2 and the ATR/ATM Pathways

The Fanconi Anemia Protein FANCM Is Controlled by FANCD2 and the ATR/ATM Pathways

Regulation of DNA cross-link repair by the Fanconi anemia/BRCA pathway

Genetic controls of DNA damage avoidance in response to acetaldehyde in fission yeast

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