RECQL4 Regulates p53 Function In Vivo During Skeletogenesis.

Abstract

RECQ DNA helicases play critical roles in maintaining genomic stability, but their role in development has been less well studied. Rothmund-Thomson syndrome, RAPADILINO, and Baller-Gerold syndrome are rare genetic disorders caused by mutations in the RECQL4 gene. These patients have significant skeletal developmental abnormalities including radial ray, limb and craniofacial defects. To investigate the role of Recql4 in the developing skeletal system, we generated Recql4 conditional knockout mice targeting the skeletal lineage. Inactivation of Recql4 using the Prx1-Cre transgene led to limb abnormalities and craniosynostosis mimicking the major bone findings in human RECQL4 patients. These Prx1-Cre(+) ;Recql4(fl/fl) mice as well as Col2a1-Cre(+) ;Recql4(fl/fl) mice exhibited growth plate defects and an increased p53 response in affected tissues. Inactivation of Trp53 in these Recql4 mutants resulted in genetic rescue of the skeletal phenotypes, indicating an in vivo interaction between Recql4 and Trp53, and p53 activation as an underlying mechanism for the developmental bone abnormalities in RECQL4 disorders. Our findings show that RECQL4 is critical for skeletal development by modulating p53 activity in vivo.

• Authors: Linchao Lu, Karine Harutyunyan, Weidong Jin, Jianhong Wu, Tao Yang, Yuqing Chen, Kyu Sang Joeng, Yangjin Bae, Jianning Tao, Brian C Dawson, Ming-Ming Jiang, Brendan Lee, Lisa L Wang
• Journal: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research (J Bone Miner Res) Vol. 30 Issue 6 Pg. 1077-89 (Jun 2015) ISSN: 1523-4681 [Electronic] United States
• PMID: 25556649 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 American Society for Bone and Mineral Research.

Chemical References

• Tumor Suppressor Protein p53
• RecQ Helicases

Topics

• Anal Canal (abnormalities, metabolism, pathology)
• Animals
• Bone Development
• Craniosynostoses (genetics, metabolism, pathology)
• Dwarfism (genetics, metabolism, pathology)
• Heart Septal Defects, Atrial (genetics, metabolism, pathology)
• Humans
• Limb Deformities, Congenital (genetics, metabolism, pathology)
• Mice
• Mice, Transgenic
• Mutation
• Patella (abnormalities, metabolism, pathology)
• Radius (abnormalities, metabolism, pathology)
• RecQ Helicases (genetics, metabolism)
• Rothmund-Thomson Syndrome (genetics, metabolism, pathology)
• Tumor Suppressor Protein p53 (genetics, metabolism)