RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1.

Bassam Abu‐Libdeh ,Vassilis Roukos,Tamar Harel,Abdulsalam Abu-Libdeh,John J Reynolds,Robert M Brosh,Claudia M Nicolae,Joshua A Sommers,Stephen J Smerdon,Karina Durlacher-Betzer,Grant S Stewart,Vardiella Meiner,Satpal S Jhujh,Srijita Dhar,Sophie Cooke ,Robert M Hollingworth ,George‐Lucian Moldovan ,Laura Grange ,Gabriel M C Longo ,Vered Molho‐Pessach ,Gavin Mcnee ,Asoke G Datta ,Beth L Woodward ,Anil Ganesh

doi:10.1172/jci147301

Abstract

Despite being the first homolog of the bacterial RecQ helicase to be identified in humans, the function of RECQL1 remains poorly characterized. Furthermore, unlike other members of the human RECQ family of helicases, mutations in RECQL1 have not been associated with a genetic disease. Here, we identify 2 families with a genome instability disorder that we have named RECON (RECql ONe) syndrome, caused by biallelic mutations in the RECQL gene. The affected individuals had short stature, progeroid facial features, a hypoplastic nose, xeroderma, and skin photosensitivity and were homozygous for the same missense mutation in RECQL1 (p.Ala459Ser), located within its zinc binding domain. Biochemical analysis of the mutant RECQL1 protein revealed that the p.A459S missense mutation compromised its ATPase, helicase, and fork restoration activity, while its capacity to promote single-strand DNA annealing was largely unaffected. At the cellular level, this mutation in RECQL1 gave rise to a defect in the ability to repair DNA damage induced by exposure to topoisomerase poisons and a failure of DNA replication to progress efficiently in the presence of abortive topoisomerase lesions. Taken together, RECQL1 is the fourth member of the RecQ family of helicases to be associated with a human genome instability disorder.

Highlights

DNA helicases are ubiquitous enzymes found in most uni- and multi-cellular organisms and function to unwind DNA in an ATP-dependent and direction-specific manner
Similar observations were reported for Recql knockout mouse embryo fibroblasts exposed to ionising radiation [13]. This phenotype was recapitulated in the RECQL1 CRISPR knockout HeLa cells and could be complemented by re-expression of wild type (WT) but not p.A459S mutant RECQL1 (Supplementary Figure 9E). These results suggest that the defective repair of CPT- or ETOP-induced DNA damage may arise either because of defective DNA damage response (DDR) signalling and/or an inability of the replisome to progress past these lesions, resulting in underreplicated DNA transiting through the cell cycle into the following G1 phase
Despite RECQL being cloned over 25 years ago [10], the role that it plays within the cell to maintain genome stability remains relatively unclear

Summary

Introduction

DNA helicases are ubiquitous enzymes found in most uni- and multi-cellular organisms and function to unwind DNA in an ATP-dependent and direction-specific manner. Biallelic mutations in three out five of these RecQ homologs, WRN, BLM and RECQL4, have been associated with rare genetic disorders in humans, characterised by chromosomal instability and cancer predisposition [1,2]. These genetic disorders are distinct with each syndrome exhibiting a unique set of clinical and cellular features. This serves to highlight that despite each of these enzymes being structurally and functionally related, they perform distinct tasks within the cell

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