CHEK1 coordinates DNA damage signaling and meiotic progression in the male germline of mice

Abstract

The continuity of life depends onmechanisms in the germline that ensure the integrity of the genome. The DNA damage response/checkpoint kinases ATM and ATR are essential signaling factors in the germline. However, it remains unknown how a downstreamtransducer, Checkpoint Kinase 1 (CHEK1 or CHK1),mediates signaling in themale germline. Here, we show that CHEK1 has distinct functions in both themitotic andmeiotic phases of themale germline inmice. In themitotic phase, CHEK1 is required for the resumption of prospermatogonia proliferation after birth and themaintenance of spermatogonia. In the meiotic phase, we uncovered two functions for CHEK1: one is the stage-specific attenuation of DNA damage signaling on autosomes, and the other is coordination ofmeiotic stage progression. On autosomes, the loss of CHEK1 delays the removal of DNA damage signaling thatmanifests as phosphorylation of histone variant H2AX at serine 139 (γH2AX). Importantly, CHEK1 does not have a direct function inmeiotic sex chromosome inactivation (MSCI), an essential event inmalemeiosis, in which ATR is a key regulator. Thus, the functions of ATR and CHEK1 are uncoupled in MSCI, in contrast to their roles in DNA damage signaling in somatic cells. Our study reveals stage-specific functions for CHEK1 that ensure the integrity of themale germline.