Ubiquitylation Drives Replisome Unloading in S-Phase and in Mitosis
1:00pm - 2:00pm /
Monday 4th November 2019
/ Venue: LT1 Life Sciences Building
- Urszula McClurg
- Suitable for: Those interested in Genomes, Systems and Therapeutic Targeting
- Admission: Free
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Speaker: Aga Gambus (University of Birmingham)
DNA replication is one of the most fundamental processes in life. However, after 65 years or research still little is known as to how eukaryotic replication is completed. Using Xenopus laevis egg extract, we have shown recently that polyubiquitylation plays a key role in the disassembly of the replication machinery once it has fulfilled its role. We have determined that one subunit of the active helicase is polyubiquitylated upon termination with K48-linked chains by Cullin2-based ubiquitin ligase, with LRR1 as a substrate receptor. The ubiquitylation is followed by removal of the helicase from chromatin in a manner dependent on p97/VCP segregase. As the helicase forms the organising centre of the replisome, its removal leads to the disassembly of the remaining replication machinery.
But what happens when the helicase is not unloaded in S-phase? We have now shown that any replisomes left on chromatin until mitosis are unloaded by a back-up pathway. Interestingly, this mitotic disassembly is regulated by a different ubiquitin ligase: TRAIP and by different types of ubiquitin chains (K6 and K63). It still, however, requires the activity of p97 segregase. This mitotic pathway is able to remove any replication machinery from charmatin including one from stalle/collapsed replication forks suggesting its high importance for maintenance of chromosomal stability.
DNA replication is one of the most fundamental processes in life. However, after 65 years or research still little is known as to how eukaryotic replication is completed. Using Xenopus laevis egg extract, we have shown recently that polyubiquitylation plays a key role in the disassembly of the replication machinery once it has fulfilled its role. We have determined that one subunit of the active helicase is polyubiquitylated upon termination with K48-linked chains by Cullin2-based ubiquitin ligase, with LRR1 as a substrate receptor. The ubiquitylation is followed by removal of the helicase from chromatin in a manner dependent on p97/VCP segregase. As the helicase forms the organising centre of the replisome, its removal leads to the disassembly of the remaining replication machinery.
But what happens when the helicase is not unloaded in S-phase? We have now shown that any replisomes left on chromatin until mitosis are unloaded by a back-up pathway. Interestingly, this mitotic disassembly is regulated by a different ubiquitin ligase: TRAIP and by different types of ubiquitin chains (K6 and K63). It still, however, requires the activity of p97 segregase. This mitotic pathway is able to remove any replication machinery from charmatin including one from stalle/collapsed replication forks suggesting its high importance for maintenance of chromosomal stability.