Distinct Roles of FANCO/RAD51C Protein in DNA Damage Signaling and Repair

Somyajit, Kumar; Subramanya, Shreelakshmi; Nagaraju, Ganesh

doi:10.1074/jbc.m111.311241

Cited by 67 publications

(38 citation statements)

References 66 publications

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“…The finding that RAD51C directly binds to PALB2 further suggests a function for this RAD51 paralog in the FA-BRCA pathway of DNA repair. Consistent with this possibility, the RAD51C missense mutant from a FA patient, R258H, displays defective co-immunoprecipitation of PALB2 and BRCA2, as well as RAD51 and XRCC3 [58, 134]. Missense mutants of RAD51C from breast cancer patients, including L138F and D159N, display similar defects.…”

Section: The C-terminus Of Palb2mentioning

confidence: 94%

PALB2: The hub of a network of tumor suppressors involved in DNA damage responses

Park

Zhang

Andreassen

2014

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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PALB2 was first identified as a partner of BRCA2 that mediates its recruitment to sites of DNA damage. PALB2 was subsequently found as a tumor suppressor gene. Inherited heterozygosity for this gene is associated with an increased risk of cancer of the breast and other sites. Additionally, biallelic mutation of PALB2 is linked to Fanconi anemia, which also has an increased risk of developing malignant disease. Recent work has identified numerous interactions of PALB2, suggesting that it functions in a network of proteins encoded by tumor suppressors. Notably, many of these tumor suppressors are related to the cellular response to DNA damage. The recruitment of PALB2 to DNA double-strand breaks at the head of this network is via a ubiquitin-dependent signaling pathway that involves the RAP80, Abraxas and BRCA1 tumor suppressors. Next, PALB2 interacts with BRCA2, which is a tumor suppressor, and with the RAD51 recombinase. These interactions promote DNA repair by homologous recombination (HR). More recently, PALB2 has been found to bind the RAD51 paralog, RAD51C, as well as the translesion polymerase pol η, both of which are tumor suppressors with functions in HR. Further, an interaction with MRG15, which is related to chromatin regulation, may facilitate DNA repair in damaged chromatin. Finally, PALB2 interacts with KEAP1, a regulator of the response to oxidative stress. The PALB2 network appears to mediate the maintenance of genome stability, may explain the association of many of the corresponding genes with similar spectra of tumors, and could present novel therapeutic opportunities.

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Section: The C-terminus Of Palb2mentioning

confidence: 94%

PALB2: The hub of a network of tumor suppressors involved in DNA damage responses

Park

Zhang

Andreassen

2014

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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“…However, in both cases, mutations have been observed in ~1% of families with BRCA1/2-negative breast and ovarian cancer. Truncating mutations have been reported for both RAD51C and RAD51D and, in addition for RAD51C , in addition to missense mutations that impair the ATP binding site (Meindl et al 2010; Loveday et al 2011; Loveday et al 2012; Somyajit et al 2012). …”

Section: Rad51 Paralogsmentioning

confidence: 99%

“…Some of the congenital abnormalities are similar to those described in FA-D1 and FA-N children with biallelic BRCA2 and PALB2 mutation, respectively; however, the absence of a malignancy in the older child is distinct (Moldovan and D'Andrea 2009). RAD51C R258 is close to the ATP binding site and is highly conserved; the mutation has been shown to reduce but not abolish HR function (Somyajit et al 2012). XRCC2 is the only other RAD51 paralog besides RAD51C for which a Fanconi anemia-like phenotype has been described to date.…”

Section: Rad51 Paralogsmentioning

confidence: 99%

Homologous Recombination and Human Health: The Roles of BRCA1, BRCA2, and Associated Proteins

Prakash

Zhang

Feng

et al. 2015

Cold Spring Harb Perspect Biol

682

673

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Homologous recombination (HR) is a major pathway for the repair of DNA double-strand breaks in mammalian cells, the defining step of which is homologous strand exchange directed by the RAD51 protein. The physiological importance of HR is underscored by the observation of genomic instability in HR-deficient cells and, importantly, the association of cancer predisposition and developmental defects with mutations in HR genes. The tumor suppressors BRCA1 and BRCA2, key players at different stages of HR, are frequently mutated in familial breast and ovarian cancers. Other HR proteins, including PALB2 and RAD51 paralogs, have also been identified as tumor suppressors. This chapter summarizes recent findings on BRCA1, BRCA2, and associated proteins involved in human disease with an emphasis on their molecular roles and interactions.

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“…RAD51C , encoding a RAD51 paralog, was identified as a Fanconi anemia complementation group (FANCO) (Vaz et al 2010). FANCO/RAD51C also functions down-stream of FANCD2 monoubiquitination and DSB formation, but is essential for HR-mediated repair of ICL-induced replication dependent DSBs (Somyajit et al 2012). Additional RAD51 paralogs, in particular XRCC2 and XRCC3 also contribute to the HR step in ICL repair (Liu et al 1998).…”

Section: Genes Implicated In Icl Repairmentioning

confidence: 99%

Advances in Understanding the Complex Mechanisms of DNA Interstrand Cross-Link Repair

Clauson

Schärer

Niedernhofer

2013

Cold Spring Harbor Perspectives in Biology

210

260

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DNA interstrand crosslinks (ICLs) are lesions caused by a variety of endogenous metabolites, environmental exposures, and cancer chemotherapeutic agents that have two reactive groups. The common feature of these diverse lesions is that two nucleotides on opposite strands are covalently joined. ICLs prevent the separation of two DNA strands and therefore essential cellular processes including DNA replication and transcription. ICLs are mainly detected in S phase when a replication fork stalls at an ICL. Damage signaling and repair of ICLs are promoted by the Fanconi anemia pathway and numerous posttranslational modifications of DNA repair and chromatin structural proteins. ICLs are also detected and repaired in non-replicating cells, although the mechanism is less clear. A unique feature of ICL repair is that both strands of DNA must be incised to completely remove the lesion. This is accomplished in sequential steps to prevent creating multiple double-strand breaks. Unhooking of an ICL from one strand is followed by translesion synthesis to fill the gap and create an intact duplex DNA, harboring a remnant of the ICL. Removal of the lesion from the second strand is likely accomplished by nucleotide excision repair. Inadequate repair of ICLs is particularly detrimental to rapidly dividing cells, explaining the bone marrow failure characteristic of Fanconi anemia and why cross-linking agents are efficacious in cancer therapy. Herein, recent advances in our understanding of ICLs and the biological responses they trigger are discussed.

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Distinct Roles of FANCO/RAD51C Protein in DNA Damage Signaling and Repair

Cited by 67 publications

References 66 publications

PALB2: The hub of a network of tumor suppressors involved in DNA damage responses

PALB2: The hub of a network of tumor suppressors involved in DNA damage responses

Homologous Recombination and Human Health: The Roles of BRCA1, BRCA2, and Associated Proteins

Advances in Understanding the Complex Mechanisms of DNA Interstrand Cross-Link Repair

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