The long-term objective of this project is to define the roles and mechanisms by which the RecQ DNA helicases regulate mitotic recombination and suppress mitotic crossover. Homologous recombination can lead to crossover, which can lead to translocations, deletions, and loss of heterozygosity (LOH), all of which have been implicated as potential cancer causing or - promoting events. Thus, in mammals, mitotic recombination is highly regulated to prevent excessive crossover. Mutations in the RecQ family member BLM give rise to Bloom syndrome; a disease typified by increased mitotic crossovers and elevated risks to cancer, underscoring the importance of RecQ helicases in the suppression of mitotic crossover and carcinogenesis. Previously, we have shown that a mouse model of Bloom syndrome has increased tumor susceptibility as a result of diminished suppression of mitotic crossover. We have now found that a second RecQ family member, mouse RecqlS, is also involved in the suppression of mitotic crossover, and that it interacts genetically with Blm in this suppression. We hypothesize that in mammals, replication demise is the primary cause of spontaneous mitotic crossover. Two independent pathways: a Blm-specific pathway and a RecqlS-specific pathway, respectively, are responsible for the restoration of stalled forks via non-recombination-based mechanism to suppress mitotic crossover and reduce cancer risk. In this application, we propose to use the knockout mouse cell lines and knockout mouse models we have created to test this hypothesis and to study the relative contributions of these two proposed pathways in the suppression of mitotic crossover and carcinogenesis. These studies will provide significant insights into the regulation of mitotic recombination and the origins of the early oncogenic LOH events during carcinogenesis.
|Zhou, Hua-Lin; Geng, Cuiyu; Luo, Guangbin et al. (2013) The p97-UBXD8 complex destabilizes mRNA by promoting release of ubiquitinated HuR from mRNP. Genes Dev 27:1046-58|
|Zhou, Hua-Lin; Hinman, Melissa N; Barron, Victoria A et al. (2011) Hu proteins regulate alternative splicing by inducing localized histone hyperacetylation in an RNA-dependent manner. Proc Natl Acad Sci U S A 108:E627-35|
|Zhou, Guangjin; Liu, Yifei; Wu, Shwu-Yuan et al. (2010) Purification of a novel RECQL5-SWI/SNF-RNAPII super complex. Int J Biochem Mol Biol 1:101-111|