|Date and Time||2020年03月11日 16:00 - 17:00|
|Venue||DB Bldg. Auditorium C1F|
|Speaker||Dr. Anne D. Donaldson|
|Affiliation||Institute of Medical Sciences, University of Aberdeen|
|Poster||click here to download(PDF)|
|Title||How RIF1 protects cells from DNA replication stress|
|The RIF1 protein was originally identified for its role in telomere length regulation, but recently has emerged as a conserved, multifunctional protein participating in numerous genome stability pathways. We are studying how RIF1 functions to control DNA replication and the cellular response to replication stress. We found that the chromosome sites at which budding yeast RIF1 is localised include replication origins and blocked replication forks. These investigations led us to identify a new role for RIF1 in protecting the nascent DNA at blocked replication forks. Remarkably, this role in nascent DNA protection is conserved from yeast to human cells.
Human cells lacking RIF1 are highly sensitive to DNA replication inhibitors such as Aphidicolin. While the effect of RIF1 in nascent DNA protection may partly explain this sensitivity, it does not fully account for the effect, since we find RIF1 must be present not just during replication stress but also in the ensuing recovery period, to promote cell survival.
The RIF1 transcript undergoes alternative splicing to produce Long and Short isoform proteins, RIF1-L and RIF1-S. We find that of these two isoforms, RIF1-L is specifically required for replication stress resistance. Moreover, we have shown that RIF1-L is required to promote the formation of 53BP1 nuclear bodies that protect incompletely replicated DNA in the aftermath of replication stress, potentially explaining the need for RIF1-L in replication stress resistance. Our results demonstrate a novel, isoform-specific role for human RIF1 in protecting chromosomes damaged by replication stress and coordinating the ongoing cell cycle response.