Regulation of genomic stability and cellular senescence by HP1ß

• Applicant: Dr. Prim B. Singh
• Subject Area: General Genetics and Functional Genome Biology
• Term: from 2006 to 2010
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 31025652

HP1 proteins are fundamental units of heterochromatin packaging that are enriched at the centromeres and the telomeres of nearly all Eukaryotic chromosomes. The first HP1 protein in mammals was isolated by the applicant and is termed HP1ß; we have recently generated a HP1ß knock-out mouse. HP1ß-/- null mutant cells exhibit genomic instability and possess aneuploid karyotypes and chromosomal rearrangements, including telomeretelomere fusions. Cells heterozygous for the mutation (HP1ß+/-) are genomically stable but escape cellular senescence. Based on these phenotypes our goal is to describe, in concrete cellular and molecular terms, how HP1ß regulates genomic instability and cellular senescence. First, we will characterize the effect of the mutation on telomere structure. Second, the interaction of HP1ß with the cohesion complex will be investigated. Cohesion dysfunction leads to segregation defects at mitosis and aneuploidy. Third, we will determine the role of HP1ß in the generation of senescence-associated heterochromatin foci that form during senescence-associated cell cycle exit. Finally, in vivo experiments are aimed at understanding the role of HP1ß in oncogene-induced sensescence, which is a protective mechanism that is thought to oppose tumourigenesis.

• DFG Programme: Research Grants