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Title: Modulation of human ATM-Chk2 and ATR-Chk1 kinases by period-1 in the response to DNA damage and the role of the single nucleotide polymorphism Per1-A962P in the response to genotoxic stress
Author: Alhussaini, Mashael
ISNI:       0000 0004 7961 3554
Awarding Body: Bangor University
Current Institution: Bangor University
Date of Award: 2019
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Human Period 1 (Per1) is a circadian clock regulator with two N-terminal PAS domains that belongs to a group of three highly related Period proteins (Per1, Per2, Per3). The main aims of this thesis are to explore the novel link between Per1 and the DNA damage signalling pathways ATM-Chk2 and ATR-Chk1, and to investigate the functional significance of the single nucleotide polymorphism (rs2585405) which replaces alanine-962 by a proline residue in the C-terminal section of human Per1. While the alanine and proline alleles have an almost 50:50 ratio in East Asia, a strong selection against the proline residue exists in Europe. In line with the previous finding that human Per1 associates with ATM and Chk2 kinases, this thesis finds a strong correlation between elevated Per1 protein levels and increased ATM-Chk2 activity in human colon carcinoma cells (HCT116) compared to embryonic kidney cells (HEK293). Isoelectric focusing experiments reveal four Per1 splice variants in HEK293 cells. Each of the two larger variants exists as a mixture of at least two forms with distinct posttranslational modifications. The abundance of both positively charged, large forms increase in the response to DNA damage. Endogenous Per1 appears to be mainly cytoplasmic in untreated and UV irradiated HEK cells. Using two stable HEK cell lines, which either express EGFP-PER1-A962 or EGFP-PER1-P962 in addition to the endogenous Per1 protein, the thesis provides evidence that a proline at position 962 reduces Chk1 phosphorylation at serine-345 in the response to UV-induced DNA damage and when DNA replication forks break in the presence of camptothecin.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Per1 ; Per2 ; Per3 ; Per1-A962