Checkpoint-Independent Regulation of Origin Firing by Mrc1 through Interaction with Hsk1 Kinase.

Seiji Matsumoto, Yutaka Kanoh, Michie Shimmoto, Motoshi Hayano, Kyosuke Ueda, Rino Fukatsu, Naoko Kakusho, Hisao Masai

Molecular and cellular biology 2017 Apr 01

filter terms:

Mrc1 is a conserved checkpoint mediator protein that transduces the replication stress signal to the downstream effector kinase. The loss of mrc1 checkpoint activity results in the aberrant activation of late/dormant origins in the presence of hydroxyurea. Mrc1 was also suggested to regulate orders of early origin firing in a checkpoint-independent manner, but its mechanism was unknown. Here we identify HBS (Hsk1 bypass segment) on Mrc1. An ΔHBS mutant does not activate late/dormant origin firing in the presence of hydroxyurea but causes the precocious and enhanced activation of weak early-firing origins during normal S-phase progression and bypasses the requirement for Hsk1 for growth. This may be caused by the disruption of intramolecular binding between HBS and NTHBS (N-terminal target of HBS). Hsk1 binds to Mrc1 through HBS and phosphorylates a segment adjacent to NTHBS, disrupting the intramolecular interaction. We propose that Mrc1 exerts a "brake" on initiation (through intramolecular interactions) and that this brake can be released (upon the loss of intramolecular interactions) by either the Hsk1-mediated phosphorylation of Mrc1 or the deletion of HBS (or a phosphomimic mutation of putative Hsk1 target serine/threonine), which can bypass the function of Hsk1 for growth. The brake mechanism may explain the checkpoint-independent regulation of early origin firing in fission yeast. Copyright © 2017 American Society for Microbiology.

Citation

Seiji Matsumoto, Yutaka Kanoh, Michie Shimmoto, Motoshi Hayano, Kyosuke Ueda, Rino Fukatsu, Naoko Kakusho, Hisao Masai. Checkpoint-Independent Regulation of Origin Firing by Mrc1 through Interaction with Hsk1 Kinase. Molecular and cellular biology. 2017 Apr 01;37(7)