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Defects in the ATR-dependent DNA damage response pathway and human syndromes

journal contribution
posted on 2023-06-07, 15:10 authored by Mark O'DriscollMark O'Driscoll
A multitude of clinically distinct human disorders exist whose underlying cause is a defect in the response to or repair of DNA damage. The clinical spectrum of these conditions provides evidence for the role of the DNA damage response (DDR) in mediating diverse processes such as genomic stability, immune system function and normal human development. Cell lines from these disorders provide a valuable resource to help dissect the consequences of compromised DDR at the molecular level. Ataxia telangiectasia and Rad3-related (ATR) and Ataxia telangiectasia Mutated (ATM) are apical protein kinases that play central roles in coordinating the cells response to DNA damage. Whilst ATM is activated by DNA double strand breaks (DSB's), ATR is activated by single stranded regions of DNA (ssDNA) which can occur, for example, during DNA replication fork stalling. There is significant functional overlap between these two kinases. In fact, they phosphorylate many of the same substrates, including p53 and Brca1. Nevertheless, ATR appears to be essential for embryonic development, unlike ATM. Mutations in ATM result in Ataxia telangiectasia (A-T) a progressive neurological disorder. Interestingly, a hypomorphic mutation in ATR is associated with Seckel syndrome, a clinically distinct disorder to that of A-T. Seckel syndrome is characterised by profound proportionate growth retardation with severe microcephaly. Why defects in these two related kinases should result in such distinct human disorders is unclear. Recently, mutations in Pericentrin/Kendrin (PCNT) have also been demonstrated in Seckel syndrome. PCNT encodes a core structural centrosomal protein. Interestingly, defective PCNT results in impaired ATR-dependent, but not ATM-dependent G2-M cell cycle checkpoint arrest. Using evidence from murine knockout studies and human cell-based work I will discuss the biological impact of compromised ATR-pathway function with the aim of trying to understand the link between genotype-phenotype in this context.


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Acta Medica Nagasakiensia




Nagasaki University School of Medicine



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  • Sussex Centre for Genome Damage Stability Publications



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