PALB2 Regulates Recombinational Repair through Chromatin Association and Oligomerization

Sy, Shirley M.-H.; Huen, Msy; Zhu, Yanjing; Chen, Junjie

doi:10.1074/jbc.m109.016717

Cited by 94 publications

(99 citation statements)

References 44 publications

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“…In addition to forming C-terminal associated complexes, BRCA1 contains a coiled-coil domain upstream of BRCT domain, which interacts with a coiled-coil domain at the N-terminus of PALB2. PALB2 associates with BRCA2 thus bridging the interaction of BRCA1 and BRCA2 [117][118][119]. The N-terminus RING domain, in addition to dimerizing with BARD1 forming an E3 ligase, this region is also reported to interact with a ubiquitin hydrolase BAP1 [120,121].…”

Section: Resultsmentioning

confidence: 99%

BRCA1 tumor suppressor network: focusing on its tail

Wang

2012

Cell & Bioscience

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Germline mutations of the BRCA1 tumor suppressor gene are a major cause of familial breast and ovarian cancer. BRCA1 plays critical roles in the DNA damage response that regulates activities of multiple repair and checkpoint pathways for maintaining genome stability. The BRCT domains of BRCA1 constitute a phospho-peptide binding domain recognizing a phospho-SPxF motif (S, serine; P, proline; × varies; F, phenylalanine). The BRCT domains are frequently targeted by clinically important mutations and most of these mutations disrupt the binding surface of the BRCT domains to phosphorylated peptides. The BRCT domain and its capability to bind phosphorylated protein is required for the tumor suppressor function of BRCA1. Through its BRCT phospho-binding ability BRCA1 forms at least three mutually exclusive complexes by binding to phosphorylated proteins Abraxas, Bach1 and CTIP. The A, B and C complexes, at lease partially undertake BRCA1's role in mechanisms of cell cycle checkpoint and DNA repair that maintain genome stability, thus may play important roles in BRCA1's tumor suppressor function.Germline mutations of the BRCA1 tumor suppressor gene are a major cause of familial breast and ovarian cancer [1,2]. BRCA1 plays critical roles in a number of diverse cellular processes that ensure genome integrity and the increase risk of breast and ovarian cancer caused by mutation of BRCA1 has been attributed to increased genomic instability. To safeguard genome, cells have evolved a defensive mechanism, called the DNA damage response (DDR), to coordinate multiple cellular responses including DNA repair, cell cycle checkpoint regulation, transcription, senescence or apoptosis etc., to counteract genotoxic stress [3][4][5][6]. BRCA1 appears to act as a central mediator of the cellular response to DNA damage that regulates the activities of multiple repair and checkpoint pathways [3,5,[7][8][9][10]. BRCA1 is a substrate of the central DNA damage response kinases ATM/ATR that control the DDR. It is required for homology directed repair, a pathway that facilitates error-free repair of double-strand breaks (DSBs) and resolution of stalled DNA replication forks through homologous recombination (HR) [9][10][11] as well as postreplicative repair in response to UV damage [12]. Recently it is suggested that much of BRCA1's role in maintaining genome stability is accounted for by its role in maintaining heterochromatin integrity via H2A ubiquitination [13].BRCA1 associates with multiple repair proteins and cell cycle regulators and such a capability to form multiple protein complexes contributes to its role in maintaining chromosome stability and tumor suppression (Figure 1). BRCA1 is a large protein of 1,863 amino acids. It contains two important domains at each end of the protein, a RING domain at the N-terminus and two BRCT domains at the C-terminus. Many clinically important mutations of BRCA1 gene frequently target these two domains. BRCA1 dimerizes with BARD1 through the RING domain present on each or the protein, forming...

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Section: Resultsmentioning

confidence: 99%

BRCA1 tumor suppressor network: focusing on its tail

Wang

2012

Cell & Bioscience

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“…Plasmids and siRNAs-HA-FLAG, Myc, and streptavidin binding peptide-FLAG (SFB)-tagged PALB2 or BRCA1 expression constructs were previously described (21,24,25). For RNAi-mediated depletion experiments, cells were transfected twice with either non-targeting control or target siRNAs (Dharmacon) using Oligofectamine according to the manufacturer's instructions (Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

“…We also took advantage of a BRCA1-binding defective PALB2 mutant that was previously characterized (⌬N42) (21,24,25), and examined how IR treatment affects PALB2 phosphorylation at Ser-157 and Ser-376 when its ability to interact with BRCA1 was compromised. Consistent with a critical role of the BRCA1-PALB2 complex formation in the DDR, defects in BRCA1-binding hampered PALB2 phosphorylation at Ser-157 (Fig.…”

Section: The Ddr Kinase Atm Is Required For Ir-induced Palb2mentioning

confidence: 99%

ATM-dependent Phosphorylation of the Fanconi Anemia Protein PALB2 Promotes the DNA Damage Response

Guo

Feng

et al. 2015

Journal of Biological Chemistry

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“…PALB2 is also recruited by BRCA1 in response to DNA damage and serves as a linker between BRCA1 and BRCA2 and is necessary for BRCA2-mediated homologous-recombination repair [97,98]. Thus, BRCA1, BRCA2 and PALB2 are key BC susceptibility genes that work together in the same DNA damage response pathway [99,100]. Leyton et al [95] studied 100 BRCA1/2-negative Chilean cases with familial BC, identifying 3 PALB2 variants.…”

Section: Other Bc Susceptibility Mutations In Central and South Amerimentioning

confidence: 99%

Mutations in BRCA1, BRCA2 and other breast and ovarian cancer susceptibility genes in Central and South American populations

et al. 2017

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Breast cancer (BC) is the most common malignancy among women worldwide. A major advance in the understanding of the genetic etiology of BC was the discovery of BRCA1 and BRCA2 (BRCA1/2) genes, which are considered high-penetrance BC genes. In non-carriers of BRCA1/2 mutations, disease susceptibility may be explained of a small number of mutations in BRCA1/2 and a much higher proportion of mutations in ethnicity-specific moderate-and/or low-penetrance genes. In Central and South American populations, studied have focused on analyzing the distribution and prevalence of BRCA1/2 mutations and other susceptibility genes that are scarce in Latin America as compared to North America, Europe, Australia, and Israel. Thus, the aim of this review is to present the current state of knowledge regarding pathogenic BRCA variants and other BC susceptibility genes. We conducted a comprehensive review of 47 studies from 12 countries in Central and South America published between 2002 and 2017 reporting the prevalence and/or spectrum of mutations and pathogenic variants in BRCA1/2 and other BC susceptibility genes. The studies on BRCA1/2 mutations screened a total of 5956 individuals, and studies on susceptibility genes analyzed a combined sample size of 11,578 individuals. To date, a total of 190 different BRCA1/2 pathogenic mutations in Central and South American populations have been reported in the literature. Pathogenic mutations or variants that increase BC risk have been reported in the following genes or genomic regions: ATM, BARD1, CHECK2, FGFR2, GSTM1, MAP3K1, MTHFR, PALB2, RAD51, TOX3, TP53, XRCC1, and 2q35.

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PALB2 Regulates Recombinational Repair through Chromatin Association and Oligomerization

Cited by 94 publications

References 44 publications

BRCA1 tumor suppressor network: focusing on its tail

BRCA1 tumor suppressor network: focusing on its tail

ATM-dependent Phosphorylation of the Fanconi Anemia Protein PALB2 Promotes the DNA Damage Response

Mutations in BRCA1, BRCA2 and other breast and ovarian cancer susceptibility genes in Central and South American populations

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