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Werner Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The localization by linkage study of the culprit gene region to chromosome 8 in 1992 and the identification by positional cloning of the WRN gene in 1996 revealed molecular insights on the pathogenesis of Werner syndrome. Indeed, these new findings helped clarify the premature aging seen in Werner syndrome as distinct from normal aging on a cellular level [3–5]. Further, the characterization of the WRN encoded product as RecQ helicase (RECQL2), one of five members (i.e., RECQL1, BLM, WRN, RECQL4, and RECQL5) in the RecQ helicase family, helped link Werner syndrome to Bloom syndrome (BLM) and Rothmund−Thomson syndrome (RECQL4), each of which features genomic instability and susceptibility to cancer, and each of which demonstrates notable differences in the characteristics of genomic instability and the sites and types of cancers associated [6,7].
The Premature Aging Characteristics of RecQ Helicases
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
Christ Ordookhanian, Taylor N. Dennis, J. Jefferson P. Perry
The faithful replication of DNA and its maintenance and correct repair is critical to perturbing genetic changes that would otherwise drive increased aging, neurodegenerative disease, and cancer [1]. The RecQ helicase family of proteins function as key cellular mediators of genomic integrity, through their various roles in DNA metabolism, which includes functions in replication, recombination, and repair [2,3]. The RecQ helicase family is named after its founding member from E. coli [4], and RecQ proteins are distributed across the domains of life [5]. Where characterized, the RecQ helicases function through ATP hydrolysis to unwind and translocate along double-stranded (ds)DNA substrate in a 3′–5′ direction. This is in addition to having single-strand annealing properties. A number of alternate, structure-specific substrates have been defined for RecQ helicases, which contain similarities to intermediates of recombination and repair, providing further support for their functions in these DNA metabolism processes [6].
Development and implementation of precision therapies targeting base-excision DNA repair in BRCA1-associated tumors
Published in Expert Review of Precision Medicine and Drug Development, 2019
Adel Alblihy, Katia A. Mesquita, Maaz T. Sadiq, Srinivasan Madhusudan
RecQ helicase proteins are a highly conserved family of proteins with a vital role in genomic stability. They include WRN, RECQL5 and BLM helicases. Changes in the expression of these genes are correlated with breast cancer, suggesting that they may be biomarkers for breast cancer [136]. High BLM mRNA and protein levels have been linked to poor breast cancer-specific survival [137]. In addition, topoisomerase 1 and WRN expression have been associated with an aggressive form of breast cancer and poor prognosis. High level of RECQL5 mRNA has been found in 34% of the breast cancers and is significantly correlated with an aggressive phonotype. Similarly, high RECQL5 protein level has been found in more than half of breast cancers and is associated with the aggressive phenotype and poor survival, although only in correlation with low RAD51 levels, highlighting the possible interaction between these two proteins. It also revealed that RECQL5 expression in noncancerous breast epithelial cells plays a role in increasing proliferation, proposing an oncogenic role in breast cancer [137]. RECQL5 is a target for monotherapy and combined therapy for cancer treatment. WRN and BLM induce synthetic lethality with other DNA damage response proteins. Moreover, the depletion of WRN and BLM have shown to increase the sensitization of cancer cells to chemotherapeutic agents [138,139].