B-type lamins and their elusive roles in metazoan cell proliferation and senescence.

Have you seen the recent papers that question the traditional role of B-type lamins in DNA replication and transcription, but highlight an entirely novel yet fundamental role for lamin B1 (LB1) in cell proliferation and cellular senescence? Lamins are the evolutionary progenitors of the intermediate filament superfamily, and constitute the building blocks of the nuclear lamina. They are also a defining feature of metazoan organisms. In vertebrates and higher invertebrates, there are two classes of lamins, namely the B-type lamins (LB1, LB2 and LB3) and the A-type lamins (LMA and LMC) (Hutchison, 2002). For years, dogma has stated that the B-type lamins have fundamental roles in cell physiology and are essential for cell survival (Harborth et al, 2001). This dogma was recently challenged by the astonishing finding that mouse embryonic stem cells devoid of B-type lamins could not only self-renew, but also differentiate (Kim et al, 2011). While the Kim study does not challenge the notion that lamins are essential for embryonic development, it nonetheless questions the reported roles for B-type lamins in basic processes such as DNA replication and transcription, leading the authors to predict a key function for B-type lamins in maintaining tissue homeostasis. Now an entirely new role for LB1 has been reported, which emphasizes its function in proliferation and longevity of somatic cells and suggests that this ubiquitous protein might indeed have evolved to support tissue homeostasis in metazoans. In this issue of The EMBO Journal, Pascal Bertrand’s team describes a novel role for LB1 in entry into an MAPK-mediated state of stress-induced premature senescence (Barascu et al, 2012). Starting from observations in cells obtained from patients with the premature ageing syndrome Ataxia Telangiectasia (A-T), the team showed that increased ROS generation and abnormally shaped nuclei, but not impaired DNA damage repair, were associated with an approximate three-fold increase in LB1 expression levels. The authors went on to show that overexpression of LB1 caused nuclear shape abnormalities and entry into a state of premature senescence in normal cells. In both normal and A-T cells, the increased expression of LB1 appeared to be caused by ROS generation, since pro-oxidant stimulation in normal cells promoted LB1 expression, while anti-oxidant treatment of A-T cells reduced LB1 expression. Finally, the team directly linked ROS-dependent increased expression of LB1 to activation of the senescence-associated p38 MAP kinase, suggesting a novel ATM-independent stress-sensing pathway that causes entry into a state of senescence. Thus, hot on the heels of the key prediction of Kim et al, the paper by Barascu and co-workers appears to have demonstrated a fundamental role for LB1 in maintaining cellular homeostasis in response to oxidative stress. Alas, cell biology is never simple! A contemporaneous paper from Bob Goldman’s laboratory reported that LB1 expression was decreased in fibroblasts that had entered states of either replicative or oncogene-induced senescence (Shimi et al, 2011). This finding was consistent with their earlier report on a dramatic loss of LB1 expression in fibroblasts from an atypical progeria patient that underwent rapid senescence (Taimen et al, 2009). In their current study,