M.Sc., Osmania University (Hyderabad, India), 1997

CHK1 is a tumor suppressor gene located on long arm of human chromosome 11 at 11q24-q24, a region marked by frequent loss of heterozygosity (LOH) in breast cancer. Studies have established that Chk1 is an evolutionary conserved serine/threonine checkpoint protein kinase, essential for mammalian development and cell viability. It senses DNA-damage due to genomic insults and arrests cells at S and G2-M phase checkpoints for DNA repair or induce cell death, thus acting as a “gatekeeper” in preventing the formation of pre-cancerous DNA lesions. Recent in vivo studies from our laboratory using multiparous conditional Chk1 mouse models have shown that haploinsufficiency of Chk1 results in accumulation of endogenous DNA damage foci and mis-coordinated cell cycle events in mammary epithelial cells, interestingly generating mammary tumors. Genetically engineered mouse models of various tumor suppressor genes such as p53, ATM, BRCA1, BRCA2 have revealed that the dosage of these genes is critical in determining breast cancer susceptibility. However, the haploinsufficient role of Chk1 in promoting breast cancer still remains a mystery and has not been investigated in-depth. In normal cycling cells, the multifunctional kinase Chk1 is critical for initiating and monitoring DNA replication during S-phase of the cell cycle. Interestingly, we have discovered unique localization patterns of Chk1 during mitosis in epithelial cells using immunostaining and analyzed by deconvolution microscopy. Our studies suggest that during mitosis, Chk1 is localized peri-chromosomally during pro-metaphase, along mid-zone during anaphase and at the midbody during telophase. Recent studies, have revealed various tumor suppressor proteins necessary for checkpoints and DNA repair such as Mad2, Brca1, Brca2, also localize and may regulate the formation of the central spindle during anaphase and progression of cytokinesis. Therefore, these “caretaker” proteins play a critical role by constantly maintaining genomic balance during cell division and prevent aberrant mitosis. Therefore, it is of utmost significance to elucidate the caretaker functions of Chk1 in regulating normal mitosis, which may be critical to prevent genomic instability, aneuploidy and breast cancer.


Relevance: Various Chk1 inhibitors such as UCN-01 are currently in clinical trials as chemotherapeutic drugs to target tumor cells. While targeting cancer cells, Chk1 inhibitors can be detrimental to homeostasis of the surrounding breast tissue and leading to ineffective treatment. Therefore, it is necessary to expedite the discovery of mitotic and tumor suppressor functions of Chk1, to aid in the design of specific anti-cancer drugs in combination with traditional radiation therapy to selectively target breast cancer cells.

Chen MS, Woodward WA, Behbod F, Peddibhotla S, Alfaro MP, Buchholz TA, Rosen JM
WNT/ß-catenin mediates radiation resistance of Sca1+ progenitors in an immortalized mammary gland cell line
JCS. 2007: 120(3):468-477. [PDF]