Microcephalin regulates BRCA2 and Rad51-associated DNA double-strand break repair.
Microcephalin (MCPH1) is a BRCA1 COOH terminal (BRCT) domain containing protein involved in the cellular response to DNA damage that has been implicated in autosomal recessive primary microcephaly. MCPH1 is recruited to sites of DNA double-strand breaks by phosphorylated histone H2AX (gammaH2AX), but the mechanism by which MCPH1 contributes to the repair process remains to be determined. Here, we show that MCPH1 binds to BRCA2 and regulates the localization of BRCA2 and Rad51 at sites of DNA damage. The interaction occurs through the NH(2) terminus of BRCA2 and the COOH terminal BRCT domains of MCPH1. Disruption of the interaction between MCPH1 and BRCA2 has no effect on the ability of BRCA2 to form a complex with Rad51 but is associated with substantially reduced levels of both BRCA2 and Rad51 at sites of DNA double-strand breaks. Uncoupling of MCPH1 from BRCA2 also interferes with Rad51-dependent and BRCA2-dependent homologous recombination repair activity. These results suggest that the role of MCPH1 in the DNA damage response is in part associated with the ability to localize BRCA2 to sites of DNA double-stand breaks.
Wu
Xianglin
X
Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
Mondal
Gourish
G
Wang
Xianshu
X
Wu
Jianmin
J
Yang
Lin
L
Pankratz
Vernon S
VS
Rowley
Matthew
M
Couch
Fergus J
FJ
D051017:Apoptosis Regulatory Proteins; D024682:BRCA2 Protein / Q000235:genetics* / Q000378:metabolism / Q000528:radiation effects; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D004249:DNA Damage / Q000528:radiation effects; D017931:DNA Primers; D004260:DNA Repair / Q000235:genetics / Q000528:radiation effects; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology* / Q000528:radiation effects; D010957:Plasmids; D034741:RNA, Small Interfering / Q000235:genetics; D051135:Rad51 Recombinase / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology / Q000528:radiation effects
D051017:Apoptosis Regulatory Proteins; C118024:BLID protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D017931:DNA Primers; C460645:MCPH1 protein, human; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D005982:Glutathione Transferase; C495153:RAD51 protein, human; D051135:Rad51 Recombinase