Daniel R. Foltz, PhD
Assembly and function of centromeric chromatin
Errors in cell division can result in cells receiving an incorrect number of chromosomes, a state known as aneuploidy. Cancer cells are frequently aneuploid and recent evidence indicates that the generation of aneuploidy can be a driving event in the development of cancer. A major cellular mechanism for avoiding aneuploidy is the tight regulation of chromosome segregation. Integral to the process of chromosome segregation is a specialized chromatin domain known as the centromere, which mediates and senses the interaction between the chromosome and spindle microtubules during cell division. This mechanism is conserved from yeast to humans. The basic unit of the centromere is a unique nucleosome that contains Centromere protein-A (CENP-A) in place of histone H3 within the histone octamer. We recently identified HJURP as the CENP-A specific chaperone required for centromere nucleosome assembly in humans. Interestingly, this protein has dual functions in centromere assembly and DNA damage repair. This finding suggests that mutation or mis-regulation of HJURP may impact multiple processes that lead to the development and progression of cancer. Chromosomal translations have been detected in prostate cancer cell lines that result in HJUPR fusion proteins. The Foltz lab is attempting to understand how HJURP targets CENP-A nucleosome assembly only to existing centromere sites, thereby avoiding the assembly of ectopic centromeres that would result in chromosome breakage-fusion cycles and gene amplification. The mis-regulation of HJUPR function may lead to the development of ectopic centromeres and would provide a clear route to aneuploidy and cancer. The formation of ectopic centromeres in cancer cells has not been well studied and may provide a mechanism by which chromosome rearrangements into non-centromere containing fragments that are otherwise lost during cell division could be stably propagated. Furthermore, they are dissecting the HJURP protein in order to understand its dual roles in the DNA damage response and CENP-A nucleosome assembly.