The goals of this proposal are to elucidate the function of two novel mammalian genes. The first of these is SNM1, a mammalian homologue of the yeast DNA repair gene. This gene is a member of the rad3 epistasis group and is known to be specifically involved in the repair of lesions produced by interstrand crosslinking agents. Evidence from studies in yeast suggests that the expression product of this gene functions in the later stages of crosslink repair to effect reconstitution of high molecular weight DNA. The second gene is most closely related to the lodestar gene of Drosophila. Studies of this gene in Drosophila suggest that it is a mitotic factor involved in the segregation of chromosomes during anaphase. The exact function of lodestar is not clear, and has been postulated to be involved in a number of processes including chromosomal condensation, DNA repair, or dissolution of the factors that maintain sister chromatid cohesion, such as DNA intertwining or protein-protein interactions. We plan to analyze the function of these genes in mammalian cells by a variety of methods. These include protein expression and localization as a function of the cell cycle, protein-protein interactions with either novel or known factors, and disruption of function through several approaches including antisense expression, conversion by chimeric oligonucleotides, and construction of homozygous -/- knockout mice.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Radiation Study Section (RAD)
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Pelroy, Richard
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University of Texas MD Anderson Cancer Center
Other Domestic Higher Education
United States
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Yan, Yiyi; Akhter, Shamima; Zhang, Xiaoshan et al. (2010) The multifunctional SNM1 gene family: not just nucleases. Future Oncol 6:1015-29
Akhter, Shamima; Lam, Yung C; Chang, Sandy et al. (2010) The telomeric protein SNM1B/Apollo is required for normal cell proliferation and embryonic development. Aging Cell 9:1047-56
Liu, Lingling; Akhter, Shamima; Bae, Jae-Bum et al. (2009) SNM1B/Apollo interacts with astrin and is required for the prophase cell cycle checkpoint. Cell Cycle 8:628-38
Bae, J-B; Mukhopadhyay, S S; Liu, L et al. (2008) Snm1B/Apollo mediates replication fork collapse and S Phase checkpoint activation in response to DNA interstrand cross-links. Oncogene 27:5045-56
Akhter, Shamima; Legerski, Randy J (2008) SNM1A acts downstream of ATM to promote the G1 cell cycle checkpoint. Biochem Biophys Res Commun 377:236-41
Geng, Liyi; Zhang, Xiaoshan; Zheng, Shu et al. (2007) Artemis links ATM to G2/M checkpoint recovery via regulation of Cdk1-cyclin B. Mol Cell Biol 27:2625-35
Ahkter, Shamima; Richie, Christopher T; Zhang, Nianxiang et al. (2005) Snm1-deficient mice exhibit accelerated tumorigenesis and susceptibility to infection. Mol Cell Biol 25:10071-8
Zhang, Xiaoshan; Succi, Janice; Feng, Zhaohui et al. (2004) Artemis is a phosphorylation target of ATM and ATR and is involved in the G2/M DNA damage checkpoint response. Mol Cell Biol 24:9207-20
Akhter, Shamima; Richie, Christopher T; Deng, Jian Min et al. (2004) Deficiency in SNM1 abolishes an early mitotic checkpoint induced by spindle stress. Mol Cell Biol 24:10448-55
Leonard, Deana; Ajuh, Paul; Lamond, Angus I et al. (2003) hLodestar/HuF2 interacts with CDC5L and is involved in pre-mRNA splicing. Biochem Biophys Res Commun 308:793-801

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