RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1
Bassam Abu-Libdeh, … , Robert M. Brosh Jr., Grant S. Stewart
Bassam Abu-Libdeh, … , Robert M. Brosh Jr., Grant S. Stewart
Published January 13, 2022
Citation Information: J Clin Invest. 2022;132(5):e147301. https://doi.org/10.1172/JCI147301.
View: Text | PDF
Research Article Cell biology Genetics

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

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.

Authors

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

×

Figure 4

Complementation of RECQL1-P1-1 fibroblasts with WT RECQL1 restores normal repair of DNA damage induced by CPT or ETOP.

Options: View larger image (or click on image) Download as PowerPoint
Complementation of RECQL1-P1-1 fibroblasts with WT RECQL1 restores norma...
(A) Quantification of 53BP1 foci in complemented patient RECQL1-P1-1 fibroblasts before and after treatment with 100 nM CPT (1 h) or 1 μM ETOP (30 min). 53BP1 foci in untreated cells and cells 24 hours after DNA damage induction were quantified in the G1 phase only (mitosin negative) to assess the amount of replication damage induced by CPT or ETOP that had transited into the following cell cycle. 53BP1 foci in cells 1 to 12 hours after DNA damage induction were quantified in the S/G2 phase only (mitosin positive) to monitor the kinetics of repair in damaged S/G2-phase cells. The mean of 3 independent experiments is shown with the SEM. A minimum of 300 cells were counted per time point. ###P < 0.001, by 2-way ANOVA with Tukey’s multiple-comparison test. (B) Micronuclei were quantified from cells described in A, before and 24 hours after exposure to CPT or ETOP. The mean of 3 independent experiments is shown with the SEM. A minimum of 500 cells were counted per time point. ##P < 0.01 and ###P < 0.001, by 2-way ANOVA with Tukey’s multiple-comparison test. (C and D) Quantification of chromosome aberrations in (C) 2 normal LCLs, 2 RECQL-mutant LCLs, and an ATLD LCL and (D) complemented patient RECQL1-P1-1 fibroblasts before and 24 hours after chronic exposure to low-dose CPT (5 nM) or ETOP (50 nM). Chromosome aberrations include chromatid/chromosome gaps and breaks, chromatid/chromosome fragments, and chromosome radials and exchanges. Representative images of each type of aberration are shown. Data show the mean ± SEM of 3 independent experiments. A minimum of 50 metaphases were counted per cell line in each experiment. #P < 0.05, ##P < 0.01, and ###P < 0.001, by 2-way ANOVA with Tukey’s multiple-comparison test (C and D).