The Werner syndrome helicase protein is required for cell proliferation, immortalization, and tumorigenesis in Scaffold Attachment Factor B1 deficient mice

Sophie Lachapelle,Steffi Oesterreich,Michel Lebel

doi:10.18632/aging.100300

Sophie Lachapelle, Steffi Oesterreich + Show 1 more

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https://doi.org/10.18632/aging.100300

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Abstract

Werner syndrome (WS) is a rare disorder characterized by the premature onset of several pathologies associated with aging. The gene responsible for WS codes for a RecQ-type DNA helicase and is believed to be involved in different aspects of DNA repair, replication, and transcription. We recently identified the Scaffold attachment factor B1 (SAFB1) as a potential interactants in human cells. SAFB1 is a multifunctional protein that binds both nucleic acids and is involved in the attachment of chromatin to the nuclear matrix, transcription, and stress response. Mice lacking SAFB1 exhibit developmental abnormalities in their lungs, high incidence of perinatal lethality, and adults develop different types of tumors. Mouse embryonic fibroblasts from Safb1-null animals are immortalized in culture. In this study, mice with a mutation in the helicase domain of the Wrn gene were crossed to Safb1-null mice. Double homozygous mutant mice exhibited increased apoptosis, a lower cell proliferation rate in their lungs and a higher incidence of perinatal death compared to Safb1-null mice. Few double homozygous mutants survived weaning and died before the age of six months. Finally, mouse embryonic fibroblasts lacking a functional Wrn helicase inhibited the immortalization of Safb1-null cells. These results indicate that an intact Wrn protein is required for immortalization and tumorigenesis in Safb1-null mice.

Highlights

Werner syndrome (WS) is a rare autosomal disease characterised by multiple progeroid features like graying and loss of hair, development of diabetes, cataracts, osteoporosis, and cardiovascular disorders at an early age [1]
The WRN protein regulates chromatin structures in concert with topoisomerase I to guard against DNA breaks and genomic instability [18]
Scaffold attachment factor B1 (SAFB1) was originally described as an scaffold-matrix attachment regions (S/MARs)-binding protein important for chromatin organization in the nucleus [22, 23]

Summary

Introduction

Werner syndrome (WS) is a rare autosomal disease characterised by multiple progeroid features like graying and loss of hair, development of diabetes, cataracts, osteoporosis, and cardiovascular disorders at an early age [1]. WS fibroblasts derived from patients exhibit genomic instability demonstrated by many chromosomal rearrangements, recombination defects, and accumulation of oxidative damage [2,3,4,5,6]. The gene responsible for WS (WRN) was identified by positional cloning and the gene product contains a domain homologous to the RecQ-type DNA helicases [9]. Accumulating evidences indicate that WRN protein is involved in DNA replication/repair, telomere maintenance, and transcription as well [3, 12,13,14,15,16,17]. The WRN protein regulates chromatin structures in concert with topoisomerase I to guard against DNA breaks and genomic instability [18]

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