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CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism for recombinational repair

Author

Listed:
  • Fumiko Esashi

    (Clare Hall Laboratories)

  • Nicole Christ

    (Memorial Sloan-Kettering Cancer Center)

  • Julian Gannon

    (Clare Hall Laboratories)

  • Yilun Liu

    (Clare Hall Laboratories)

  • Tim Hunt

    (Clare Hall Laboratories)

  • Maria Jasin

    (Memorial Sloan-Kettering Cancer Center)

  • Stephen C. West

    (Clare Hall Laboratories)

Abstract

Inherited mutations in BRCA2 are associated with a predisposition to early-onset breast cancers. The underlying basis of tumorigenesis is thought to be linked to defects in DNA double-strand break repair by homologous recombination. Here we show that the carboxy-terminal region of BRCA2, which interacts directly with the essential recombination protein RAD51, contains a site (serine 3291; S3291) that is phosphorylated by cyclin-dependent kinases. Phosphorylation of S3291 is low in S phase when recombination is active, but increases as cells progress towards mitosis. This modification blocks C-terminal interactions between BRCA2 and RAD51. However, DNA damage overcomes cell cycle regulation by decreasing S3291 phosphorylation and stimulating interactions with RAD51. These results indicate that S3291 phosphorylation might provide a molecular switch to regulate RAD51 recombination activity, providing new insight into why BRCA2 C-terminal deletions lead to radiation sensitivity and cancer predisposition.

Suggested Citation

  • Fumiko Esashi & Nicole Christ & Julian Gannon & Yilun Liu & Tim Hunt & Maria Jasin & Stephen C. West, 2005. "CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism for recombinational repair," Nature, Nature, vol. 434(7033), pages 598-604, March.
    • Handle: RePEc:nat:nature:v:434:y:2005:i:7033:d:10.1038_nature03404
    DOI: 10.1038/nature03404
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    Cited by:

    1. Poonam Roshan & Sahiti Kuppa & Jenna R. Mattice & Vikas Kaushik & Rahul Chadda & Nilisha Pokhrel & Brunda R. Tumala & Aparna Biswas & Brian Bothner & Edwin Antony & Sofia Origanti, 2023. "An Aurora B-RPA signaling axis secures chromosome segregation fidelity," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Robert Appleby & Luay Joudeh & Katie Cobbett & Luca Pellegrini, 2023. "Structural basis for stabilisation of the RAD51 nucleoprotein filament by BRCA2," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    3. James M. Dunce & Owen R. Davies, 2024. "BRCA2 stabilises RAD51 and DMC1 nucleoprotein filaments through a conserved interaction mode," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    4. Sameer Bikram Shah & Youhang Li & Shibo Li & Qing Hu & Tong Wu & Yanmeng Shi & Tran Nguyen & Isaac Ive & Linda Shi & Hailong Wang & Xiaohua Wu, 2024. "53BP1 deficiency leads to hyperrecombination using break-induced replication (BIR)," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    5. Youngho Kwon & Heike Rösner & Weixing Zhao & Platon Selemenakis & Zhuoling He & Ajinkya S. Kawale & Jeffrey N. Katz & Cody M. Rogers & Francisco E. Neal & Aida Badamchi Shabestari & Valdemaras Petrosi, 2023. "DNA binding and RAD51 engagement by the BRCA2 C-terminus orchestrate DNA repair and replication fork preservation," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    6. Yuxin Huang & Wenjing Li & Tzeh Foo & Jae-Hoon Ji & Bo Wu & Nozomi Tomimatsu & Qingming Fang & Boya Gao & Melissa Long & Jingfei Xu & Rouf Maqbool & Bipasha Mukherjee & Tengyang Ni & Salvador Alejo & , 2024. "DSS1 restrains BRCA2’s engagement with dsDNA for homologous recombination, replication fork protection, and R-loop homeostasis," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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