Protection of genome integrity is critical for preventing genetic mutations and chromosomal rearrangements that can lead to cancer, aging-related disorders, neurological, immunological and developmental diseases, infertility, birth defects and many other disorders. DNA damage triggers the checkpoint kinases ATM and ATR to phosphorylate the C-terminus of histone H2AX in chromatin flanking DNA lesions. This phospho-H2AX, known as gamma-H2AX, serves as a signaling and protein docking platform to regulate DNA repair and cell cycle checkpoint activities. While gamma-H2AX has well known roles at DNA double- strand breaks created by ionizing radiation and other clastogens, its role at stalled or damaged replication forks during the DNA synthesis (S)-phase of the cell cycle is enigmatic. We recently discovered that gamma-HAX recruits the genome maintenance factor Brc1 to stalled or damaged replication forks. We also found that Brc1 binding to gamma-H2AX is crucial in the absence of Rqh1, which is the ortholog of human BLM DNA helicase that is mutated in Bloom's Syndrome. In this project we propose to: (1), discover why ?H2AX is crucial when Rqh1 DNA helicase is defective;(2), define and characterize the genetic deficiencies that create a critical requirement for ?H2AX and Brc1;(3), assess the functions of the electronegative surface in the BRCT5-6 interdomain linker of Brc1. The impact of these studies will be to significantly improve the understanding of how genome integrity is protected in S-phase.

Public Health Relevance

Human health depends on genome maintenance mechanisms that insure the accurate reproduction and distribution of genetic blueprints during each of the ~10,000 trillion cell divisions in the average human lifetime. These will uncover crucial insights into these mechanisms, thereby increasing the probability of developing new strategies for treating cancer and other diseases caused by genome instability.

National Institute of Health (NIH)
Research Project (R01)
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Molecular Genetics B Study Section (MGB)
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Reddy, Michael K
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Scripps Research Institute
La Jolla
United States
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Wei, Yi; Wang, Hai-Tao; Zhai, Yonggong et al. (2014) Mdb1, a fission yeast homolog of human MDC1, modulates DNA damage response and mitotic spindle function. PLoS One 9:e97028
Dehe, Pierre-Marie; Coulon, Stephane; Scaglione, Sarah et al. (2013) Regulation of Mus81-Eme1 Holliday junction resolvase in response to DNA damage. Nat Struct Mol Biol 20:598-603
Lee, Si Young; Rozenzhak, Sophie; Russell, Paul (2013) ?H2A-binding protein Brc1 affects centromere function in fission yeast. Mol Cell Biol 33:1410-6
Lee, Si Young; Russell, Paul (2013) Brc1 links replication stress response and centromere function. Cell Cycle 12:1665-71
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Rozenzhak, Sophie; Mejia-Ramirez, Eva; Williams, Jessica S et al. (2010) Rad3 decorates critical chromosomal domains with gammaH2A to protect genome integrity during S-Phase in fission yeast. PLoS Genet 6:e1001032
Sofueva, Sevil; Du, Li-Lin; Limbo, Oliver et al. (2010) BRCT domain interactions with phospho-histone H2A target Crb2 to chromatin at double-strand breaks and maintain the DNA damage checkpoint. Mol Cell Biol 30:4732-43

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