Altered modulation of lamin A/C‐HDAC2 interaction and p21 expression during oxidative stress response in HGPS

• Published in: Aging cell Vol. 17; no. 5; pp. e12824 - n/a
• Main Authors: Mattioli, Elisabetta, Andrenacci, Davide, Garofalo, Cecilia, Prencipe, Sabino, Scotlandi, Katia, Remondini, Daniel, Gentilini, Davide, Di Blasio, Anna Maria, Valente, Sergio, Scarano, Emanuela, Cicchilitti, Lucia, Piaggio, Giulia, Mai, Antonello, Lattanzi, Giovanna
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.10.2018; John Wiley and Sons Inc
• Subjects: Acetylation; Adolescent; Aged; Aging; Bone resorption; CDKN1A (p21WAF1/Cip1); Cells, Cultured; Child; Child, Preschool; Chromatin; Cyclin-dependent kinase inhibitor p21; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; DNA Damage; DNA Repair; Female; Fibroblasts; Fibroblasts - metabolism; Fibroblasts - pathology; Gene Expression Regulation; HDAC2 protein; Histone deacetylase; histone deacetylase 2 (HDAC2); Histone Deacetylase 2 - metabolism; Humans; Hutchinson–Gilford progeria syndrome (HGPS); lamin A/C; Lamin Type A - metabolism; Male; Mutation - genetics; Original; Oxidative Stress; Phenotypes; Physiological aspects; Progeria; Progeria - genetics; Progeria - metabolism; Progeria - pathology; Protein Binding; Senescence; Skin; Stress response; Substrate Specificity; Therapeutic applications; lamin A/C; histone deacetylase 2 (HDAC2); Hutchinson-Gilford progeria syndrome (HGPS); aging; CDKN1A (p21WAF1/Cip1); oxidative stress
• ISSN: 1474-9718; 1474-9726
• DOI: 10.1111/acel.12824

Defects in stress response are main determinants of cellular senescence and organism aging. In fibroblasts from patients affected by Hutchinson–Gilford progeria, a severe LMNA‐linked syndrome associated with bone resorption, cardiovascular disorders, and premature aging, we found altered modulation of CDKN1A, encoding p21, upon oxidative stress induction, and accumulation of senescence markers during stress recovery. In this context, we unraveled a dynamic interaction of lamin A/C with HDAC2, an histone deacetylase that regulates CDKN1A expression. In control skin fibroblasts, lamin A/C is part of a protein complex including HDAC2 and its histone substrates; protein interaction is reduced at the onset of DNA damage response and recovered after completion of DNA repair. This interplay parallels modulation of p21 expression and global histone acetylation, and it is disrupted by LMNAmutations leading to progeroid phenotypes. In fact, HGPS cells show impaired lamin A/C‐HDAC2 interplay and accumulation of p21 upon stress recovery. Collectively, these results link altered physical interaction between lamin A/C and HDAC2 to cellular and organism aging. The lamin A/C‐HDAC2 complex may be a novel therapeutic target to slow down progression of progeria symptoms.