School of Life Sciences

Chan Lab

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Chromosome Dynamics and Stability Group

Current recruitment

A long-term postdoctoral research position (3 years + potential extension if progress is satisfied) is available in November 2022. 

The preservation of genome integrity is of paramount importance for the continuity of life. This is achieved through a series of highly coordinated cellular processes including accurate DNA replication, repair, and faithful chromosome segregation. Our group is interested in the interplay between DNA replication and chromosome segregation, and in how cells equally distribute sister chromatids during mitosis. We study the mechanisms of sister chromatids cohesion, chromosome biorientation, and disjunction. Notably, we focus on how sister-DNA intertwining structures influence chromosome segregation and integrity. Accumulating evidence has shown that disturbance of these processes can lead to transgenerational DNA lesions. We thus also investigate how mitosis-associated DNA damage may initiate cancer genome evolution. By employing high/super-resolution microscopy, we study how different parts of human chromosomes change during mitosis under normal or replication stress conditions. Additionally, combining CRISPR genome-editing techniques and conditional chemical inhibition, we study how mitotic kinases including Polo-like kinase 1 and Aurora B participate in chromosome protection, and the resolution of sister DNA intertwinements, also known as ultrafine DNA bridges (UFBs). We believe that the misregulation of chromosome maintenance pathways in mitosis is one of the driving forces to gross genome rearrangements, leading to cell transformation and some rare human genetic disorders. 

Below: Using super-resolution gated-STED microscopy to locate ongoing DNA replication forks (co-labelled by EdU and RPA)

RPA on EdU tracks

Below: HeLa anaphase cells expressing hypomorphic 53BP1 protein exhibit sister chromatids intertwining and rupture (red: gammaH2AX; green: PICH)  

B2_PICHgH2AX

Below: Human RPE1 cells lose centromere integrity in early mitosis when Polo-like kinase 1 function is compromised. This results in severe breakages at centromeres, leading to the formation of centromeric DNA threads coated by PICH translocase and whole chromosome arm separation (Grey, centromeres; Red, RPA; Green, PICH translocase). 

RPE1 cells treated with BI2536

Below: Mitotic chromosomes of human diploid epithelium cells labelled with multiple-colour FISH probes for chromosome rearrangements analysis.

mFISH_RPE1 

Below: Bloom's syndrome helicase (BLM) deficient cells show significant increases in sister chromatids exchange (SCE).

HAP1 BLM SCE

 


 

 

 

 

 

 

 

 

 

 

 

 

 

 

 Our research is supported by  Wellcome Trust Logo   

 

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