The pathological consequences of impaired genome integrity in humans; disorders of the DNA replication machinery

O'Driscoll, Mark (2017) The pathological consequences of impaired genome integrity in humans; disorders of the DNA replication machinery. Journal of Pathology, 241 (2). pp. 192-207. ISSN 0022-3417

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Accurate and efficient replication of the human genome occurs in the context of an array of constitutional barriers, including regional topological constraints imposed by chromatin architecture and processes such as transcription, catenation of the helical polymer and spontaneously generated DNA lesions, including base modifications and strand breaks. DNA replication is fundamentally important for tissue development and homeostasis; differentiation programmes are intimately linked with stem cell division. Unsurprisingly, impairments of the DNA replication machinery can have catastrophic consequences for genome stability and cell division. Functional impacts on DNA replication and genome stability have long been known to play roles in malignant transformation through a variety of complex mechanisms, and significant further insights have been gained from studying model organisms in this context. Congenital hypomorphic defects in components of the DNA replication machinery have been and continue to be identified in humans. These disorders present with a wide range of clinical features. Indeed, in some instances, different mutations in the same gene underlie different clinical presentations. Understanding the origin and molecular basis of these features opens a window onto the range of developmental impacts of suboptimal DNA replication and genome instability in humans. Here, I will briefly overview the basic steps involved in DNA replication and the key concepts that have emerged from this area of research, before switching emphasis to the pathological consequences of defects within the DNA replication network; the human disorders.

Item Type: Article
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Research Centres and Groups: Genome Damage and Stability Centre
Subjects: Q Science
Q Science > QM Human anatomy > QM0001 General
Q Science > QM Human anatomy > QM0531 Regional anatomy
Q Science > QM Human anatomy > QM0601 Human embryology
Q Science > QP Physiology
Q Science > QP Physiology > QP0351 Neurophysiology and neuropsychology > QP0361 Nervous system
Depositing User: Mark O'Driscoll
Date Deposited: 19 Dec 2016 15:19
Last Modified: 13 Jul 2018 12:37

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