Context
To ensure genomic stability and therefore protection against tumoral development, cells have established a complex network of metabolic pathways coordinating the control of cell cycle, DNA repair, apoptosis and senescence. This network constitutes the DNA damage response (DDR).
Double strand breaks are the most toxic lesions. Homologous recombination and Non-homologous end joining (NHEJ) constitute the major pathways of double-strand break repair (DSBR). Since numerous years, the team is interested in analyzing the mechanisms of DSBR. By using intrachromosomal substrates, the team contributed to characterize the alternative pathway of NHEJ (Guirouilh-Barbat et al, 2004, 2007), and especially identify the role of Mre11 (Rass et al, 2009) in this mechanism and participated to identify the role of 53BP1 and BLM in the control of DSBR (Grabarz et al, 2013).
More recently the team focus on DSB repair and senescence in relation with the integrity of nuclear membrane.
It has been commonly proposed that senescence prevents the proliferation of cells bearing damaged DNA, thus constituting a barrier against tumour development. However, senescence is a double-edged sword, as recent data have proposed that senescent cells could favour tumour proliferation by secreting inflammatory factors. Thus, the different pathways controlling senescence should be tightly controlled and coordinated. Since the free radical theory of aging proposed by Harman in the 1950’s, oxidative stress (OS) remains one of the most frequently cited causes for aging. However, the precise molecular control of senescence induced by OS is far from being fully elucidated. In addition to OS, telomere erosion, defects in the DDR and alterations in the nuclear architecture are also associated with premature aging. The potential interplay between these different processes leading to senescence remains poorly understood, and no unifying model can be constructed. Progeroid syndromes have often been classified into two categories: laminopathies, such as Hutchinson-Gilford progeria (HGP) syndrome, associated with alterations in nuclear shape resulting from the deregulation of lamin A/Cand the DDR defect syndromes, such as Ataxia telangiectasia (AT). Lamins A/C, B1 and B2 are the major constituents of the lamina, which lines the inner nuclear membrane and determines its shape and integrity. Based on their localisation at the nuclear periphery, lamins modulate gene expression either by interacting with chromatin or by sequestering transcription factors. Additionally, other roles for lamina in the control of mitosis, DNA replication or the DNA damage response have more recently emerged. Because defects in lamin A result in the alteration of DDR, it was proposed that the two types of syndromes both undergo senescence through the accumulation of unprocessed DNA damage.
| | Recent contribution
We recently discover a new mechanism of senescence linking oxidative stress and nuclear architecture alteration.
We show that the lamin B1 protein accumulates in AT cells, in which we also recorded frequent nuclear shape alterations (NSA). Importantly, lamin B1 over-expression is sufficient to induce NSA and senescence in wild-type cells. Moreover normalizing lamin B1 levels in A-T reciprocally reduced both NSA and senescence. We further showed that lamin B1 protein accumulation is induced by oxidative stress through p38 MAPK activation. These data underline the pivotal role of lamin B1 in the induction of senescence in A-T cells (Barascu et al., 2012). Our study support a model in which lamin B1 transiently accumulates in response to ROS to protects cells against oxidative stress. However, in case of persistent and chronic ROS (e.g in A-T) the prolonged high levels of lamin B1 would lead to deleterious consequences by affecting nuclear architecture and triggering senescence. Since, deregulation of lamin A is associated with a persistence of DNA damage, it is also tempting to speculate that overexpression of lamin B1, by altering nuclear architecture, could aggravates defects of DNA signalling and repair in pathologies associated with elevated oxidative stress (i.e, A-T).
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