High impact information on MRC1

• Surprisingly, pausing does not require Mrc1, although Tof1 and Csm3 are both important [1].
• Mrc1 is a replication fork component whose phosphorylation in response to DNA replication stress activates Rad53 [2].
• In the presence of replication blocks, we find that Mec1 is recruited to regions of stalled replication, where it encounters and presumably phosphorylates Mrc1 [2].
• Blocking initiation of DNA replication blocks Mrc1 loading onto origins, providing an explanation for why so many mutants in DNA replication show checkpoint defects [2].
• Analysis of genetic interactions with Rrm3, a DNA helicase required to resolve paused forks, indicates that Mrc1 checkpoint signaling is dispensable for the resolution of stalled replication forks and suggests that replication forks lacking Mrc1 create DNA damage that must be repaired by Rrm3 [3].

Biological context of MRC1

• Mrc1 transduces signals of DNA replication stress to activate Rad53 [4].
• Activation of Mrc1, a mediator of the replication checkpoint, by telomere erosion [5].
• However, unexpectedly, given the formation of an active Rad53-Mrc1 complex in tlc1Delta rad9Delta cells, Mrc1 did not mediate the cell-cycle arrest elicited by telomerase loss [5].
• These findings elucidate a central role for Mrc1 in normal replisome function, which is distinct from its role as a checkpoint mediator, but nevertheless critical to genome stability [3].
• S-phase checkpoint proteins Tof1 and Mrc1 form a stable replication-pausing complex [6].

Associations of MRC1 with chemical compounds

• The critical role of Mrc1p in HU is therefore to promote fork recovery in a Rad53p-independent manner, presumably through the formation of a stable fork-pausing complex [7].
• Here we report that the Mediator protein Mrc1, which is required for normal DNA replication and for activation of Rad53, is present at replication forks [2].

Regulatory relationships of MRC1

• Thus, during elongation, Mrc1 may negatively regulate Cdc45 and MCM helicase to render stalled forks capable of resuming replication [8].

Other interactions of MRC1

• The yeast checkpoint factors Mrc1p and Tof1p travel with the replication fork and mediate the activation of the Rad53p kinase in response to a replication stress [7].
• Mrc1 is required for sister chromatid cohesion to aid in recombination repair of spontaneous damage [9].
• Activation of Rad53 by either Mrc1 or Rad9 contributes to the survival of clb5Delta cells, suggesting that both DNA replication and damage pathways are responsive to the decreased origin usage [10].
• Our results support the view that Mrc1 plays a specific role in DNA replication, promoting the Srs2 recruitment to PCNA independently of checkpoint signaling [11].
• Replication checkpoint protein Mrc1 is regulated by Rad3 and Tel1 in fission yeast [12].
• The rate of progression of DNA replication forks is greatly reduced in the absence of Mrc1 but much less affected by loss of Tof1 [13].

References