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2022_Sulaiman_NA_PhD.pdf (8.05 MB)

Understanding the Mechanism of Recruitment of Esco1 and Esco2 to Cohesin

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posted on 2023-05-11, 09:42 authored by Nurul Atiqah Sulaiman

For cells to faithfully transmit their genetic material to the daughter cells, chromosome segregation during mitosis must be accurately and timely executed. One way to ensure this is by keeping the duplicated chromosomes (sister chromatids) together until they are separated at the metaphase-to-anaphase transition. Sister chromatids are held together by a cohesin complex, comprising Smc1, Smc3, Scc1 and SA1/2. Several proteins associate with cohesin to govern the cohesive state of sister chromatids and regulate chromosome segregation. Two acetyltransferases, Esco1 and Esco2, associate with cohesin in a cell cycle dependent manner to establish sister chromatid cohesion by acetylating Smc3. A loss-of-function mutation of Esco2 has been identified as the underlying cause of a genetic disorder, Roberts syndrome, and overexpression of Esco1 and Esco2 has been reported in several cancers. However, the regulation of Esco1 and Esco2 and their mechanism of recruitment to chromatin in human cells is still not fully understood.

Therefore, in my research, I aimed to investigate the mechanism by which Esco1 and Esco2 are recruited to chromatin during the cell cycle and the effect of their overexpression on the cell cycle. I show that Esco1 and Esco2 are recruited to chromatin during DNA replication to acetylate Smc3. Through co-immunoprecipitation and pull-down assays, I demonstrate a novel interaction between human Esco1 and the MCM complex and PCNA and confirm a previously known interaction of Esco1 with cohesin and Pds5A/B during DNA replication. In contrast, I found that Esco2 interacts with the same set of proteins, but not with PCNA and Pds5B. For the first time, I show that overexpression of Esco1 and Esco2 in HeLa cells may induce apoptosis and that Esco2 overexpression, particularly, inhibits DNA replication. Additionally, my preliminary experiment indicates that Esco1 and Esco2 protein levels may increase in response to DNA damage.

History

Supervisor(s)

Rajnikant Patel, Sally Prigent

Date of award

2023-01-24

Author affiliation

Department of Molecular and Cell Biology

Awarding institution

University of Leicester

Qualification level

  • Doctoral

Qualification name

  • PhD

Language

en

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