Checkpoint kinase 1 is essential for fetal and adult hematopoiesis

ABSTRACT: Checkpoint-kinase 1 (CHK1) is critical for S-phase fidelity and preventing premature mitotic entry in the presence of DNA damage. Tumour cells have developed a strong dependence on CHK1 for survival and hence this kinase has developed into a promising drug-target. Chk1-deficiency in mice results in blastocyst death due to G2/M checkpoint-failure showing that it is an essential gene and may be difficult to target therapeutically. Here, we show that chemical inhibition of CHK1 kills murine and human hematopoietic stem and progenitor cells (HSPCs) by the induction of BCL2-regulated apoptosis. Cell death in HSPCs is independent of p53 but requires the BH3-only proteins BIM, PUMA and NOXA. Moreover, Chk1 is essential for definitive hematopoiesis in the embryo. Noteworthy, cell death inhibition

SUBMITTER: Prof. Andreas Villunger 

PROVIDER: S-SCDT-EMBOR-2018-47026V1 | biostudies-other |

REPOSITORIES: biostudies-other