Tho, Lye Mun
Investigating the role of Chk1 in mouse skin homeostasis and tumourigenesis.
PhD thesis, University of Glasgow.
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Chk1 is a key regulator of DNA damage response and genome stability in eukaryotes. To better understand how checkpoint proficiency affects cancer development particularly tumours induced by chemical carcinogens in murine skin, I investigated the effect of conditional genetic ablation of chk1. I found that complete deletion of chk1 immediately prior to carcinogen exposure strongly suppressed papilloma formation, and the few, small lesions that did form always retained Chk1 expression. Remarkably, chk1 deletion was accompanied by spontaneous cell proliferation followed by DNA damage and cell death within the hair follicle. This also affected and led to proliferation and ultimately depletion of label-retaining stem cells (LRCs) within the bulge region of hair follicles, the principal source for carcinogen-induced tumours. At later times, ablated skin became progressively repopulated by Chk1-expressing cells and normal sensitivity to tumour induction was restored if carcinogen treatment was delayed. In marked contrast, papillomas formed normally in chk1 hemizygous skin but showed an increased propensity to progress to carcinomas. I conclude that Chk1 is essential for the survival of incipient cancer cells but that partial loss of function (haploinsufficiency) fosters tumour progression.
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