BRCA1 and BRCA2 are nuclear polypeptides to suppress familial breast and ovarian cancers. Accumulated evidence suggests that both BRCA1 and BRCA2 participate in DNA damage response and maintain genomic stability. Mutations of BRCA1 and BRCA2 abrogate DNA damage repair and cause genomic instability under genotoxic stress, which eventually induces tumorigenesis. However, the molecular mechanism by which BRCA1 and BRCA2 participate in DNA damage response remain elusive, which impairs the irradiation of familial breast and ovarian cancers. Recently, we and others identified that PALB2 is an important adaptor that links BRCA1 and BRCA2 in a linear DNA damage repair pathway. Moreover, like BRCA1 and BRCA2, germline mutations of PALB2 are associated with familial breast and ovarian cancers, suggesting that PALB2 is a bona fide tumor suppressor. To elucidate the function of this BRCA pathway in DNA damage response and tumor suppression, our research focuses on the molecular mechanism of PALB2. Using unbiased protein affinity purification approach, we identified several PALB2 partners. Our preliminary study indicates that PALB2 is a double-strand DNA binding protein and plays an important role in DNA damage-induced histone acetylation and chromatin remodeling. In this project, we plan to: 1) dissect the molecular mechanism of PALB2 in DNA damage-induced chromatin remodeling;2) examine the functional defects of cancer-associated PALB2 mutations;3) explore novel therapeutic strategies to prevent PALB2 deficiency-induced tumorigenesis. These studies will not only reveal the molecular mechanism of BRCA pathway in DNA damage response, but also translate our knowledge from basic science research into tumor prevention.
Mutations of BRCA1 and BRCA2 associate with familial breast and ovarian cancers. Accumulated evidence suggests that both BRCA1 and BRCA2 participate in DNA damage response. However, the molecular mechanism of BRCA1 and BRCA2 in DNA damage response remains elusive. Recently, we and others found that PALB2 is an important adaptor that links BRCA1 and BRCA2 in DNA damage repair. In this proposal, we plan to dissect the molecular mechanism of PALB2 in DNA damage repair. This study is likely to reveal the novel function of the BRCA pathway in DNA damage response. The results may also lead to design novel strategies for tumor prevention.
|Li, M; Yu, X (2015) The role of poly(ADP-ribosyl)ation in DNA damage response and cancer chemotherapy. Oncogene 34:3349-56|
|Luo, Tao; Cui, Shijun; Bian, Chunjing et al. (2014) Crosstalk between TGF-?/Smad3 and BMP/BMPR2 signaling pathways via miR-17-92 cluster in carotid artery restenosis. Mol Cell Biochem 389:169-76|
|Bian, Chunjing; Yu, Xiaochun (2014) PGC7 suppresses TET3 for protecting DNA methylation. Nucleic Acids Res 42:2893-905|
|Chen, Yibin; Chen, Qiang; McEachin, Richard C et al. (2014) H2A.B facilitates transcription elongation at methylated CpG loci. Genome Res 24:570-9|
|Zhang, Feng; Chen, Yibin; Li, Mo et al. (2014) The oligonucleotide/oligosaccharide-binding fold motif is a poly(ADP-ribose)-binding domain that mediates DNA damage response. Proc Natl Acad Sci U S A 111:7278-83|
|Osterman, Michael; Kathawa, Deion; Liu, Diangang et al. (2014) Elevated DNA damage response in pancreatic cancer. Histochem Cell Biol 142:713-20|
|Li, Mo; Yu, Xiaochun (2013) Function of BRCA1 in the DNA damage response is mediated by ADP-ribosylation. Cancer Cell 23:693-704|
|Li, Mo; Lu, Lin-Yu; Yang, Chao-Yie et al. (2013) The FHA and BRCT domains recognize ADP-ribosylation during DNA damage response. Genes Dev 27:1752-68|
|Chen, Qiang; Chen, Yibin; Bian, Chunjing et al. (2013) TET2 promotes histone O-GlcNAcylation during gene transcription. Nature 493:561-4|
|Liu, Chao; Wu, Jiaxue; Paudyal, Sharad C et al. (2013) CHFR is important for the first wave of ubiquitination at DNA damage sites. Nucleic Acids Res 41:1698-710|
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