The nuclear matrix protein lamin A is a multifunctional protein with roles in DNA replication and repair, gene activation, transcriptional regulation, and maintenance of higher-order chromatin structure. Phosphorylation is the main determinant of lamin A mobility in the nucleus and nuclear membrane dissolution during mitosis. However, little is known about the regulation of lamin A phosphorylation during interphase. Interestingly, C-terminal lamin A mutations trigger cellular senescence. Recently, we showed that the C-terminal region of lamin A interacts with casein kinase II (CK2). In the present study, we have expanded on our previous research to further investigate lamin A phosphorylation and elucidate the mechanisms underlying the effect of C-terminal mutations on cellular senescence. Our results indicate that glycogen synthase kinase 3β (GSK3β) and CK2 jointly mediate the phosphorylation of lamin A at C-terminal Ser628 and Ser636 residues. Furthermore, a loss of phosphorylation at either of these two sites affects the nuclear distribution of lamin A, leading to an impaired DNA damage response as well as cellular senescence. Thus, phosphorylation at C-terminal sites in lamin A appears to be important for maintaining genomic stability and preventing cellular senescence. These findings provide insight into how loss of the C-terminal region of lamin A may induce premature aging. Furthermore, enhancement of GSK3β and CK2 activity may represent a possible therapeutic approach for the treatment of aging-related diseases.

Defective nuclear lamina protein lamin A is associated with premature aging. Casein kinase 2 (CK2) binds the nuclear lamina, and inhibiting CK2 activity induces cellular senescence in cancer cells. Thus, it is feasible that lamin A and CK2 may cooperate in the aging process. Nuclear CK2 localization relies on lamin A and the lamin A carboxyl terminus physically interacts with the CK2α catalytic core and inhibits its kinase activity. Loss of lamin A in Lmna-knockout mouse embryonic fibroblasts (MEFs) confers increased CK2 activity. Conversely, prelamin A that accumulates in Zmpste24-deficent MEFs exhibits a high CK2α binding affinity and concomitantly reduces CK2 kinase activity. Permidine treatment activates CK2 by releasing the interaction between lamin A and CK2, promoting DNA damage repair and ameliorating progeroid features. These data reveal a previously unidentified function for nuclear lamin A and highlight an essential role for CK2 in regulating senescence and aging.