A Link between Replicative Stress, Lamin Proteins, and Inflammation

Abstract

Double-stranded breaks (DSB), the most toxic DNA lesions, are either a consequence of cellular metabolism, programmed as in during V(D)J recombination, or induced by anti-tumoral therapies or accidental genotoxic exposure. One origin of DSB sources is replicative stress, a major source of genome instability, especially when the integrity of the replication forks is not properly guaranteed. To complete stalled replication, restarting the fork requires complex molecular mechanisms, such as protection, remodeling, and processing. Recently, a link has been made between DNA damage accumulation and inflammation. Indeed, defects in DNA repair or in replication can lead to the release of DNA fragments in the cytosol. The recognition of this self-DNA by DNA sensors leads to the production of inflammatory factors. This beneficial response activating an innate immune response and destruction of cells bearing DNA damage may be considered as a novel part of DNA damage response. However, upon accumulation of DNA damage, a chronic inflammatory cellular microenvironment may lead to inflammatory pathologies, aging, and progression of tumor cells. Progress in understanding the molecular mechanisms of DNA damage repair, replication stress, and cytosolic DNA production would allow to propose new therapeutical strategies against cancer or inflammatory diseases associated with aging. In this review, we describe the mechanisms involved in DSB repair, the replicative stress management, and its consequences. We also focus on new emerging links between key components of the nuclear envelope, the lamins, and DNA repair, management of replicative stress, and inflammation.

Pervasive nuclear envelope ruptures precede ECM signaling and disease onset without activating cGAS-STING in Lamin-cardiomyopathy mice

“…The lack of robust cGAS expression may reduce pathogen-derived DNA sensing in adult cardiomyocytes, similar to hepatocytes that also lack functional cGAS-STING 78 . Many reports suggest an association between DNA damage and cGAS-STING activation 27,[79][80][81][82] . Our data that Lmna CKO cardiomyocytes accumulate DNA damage without activating cGAS-STING suggest that DNA damage and cGAS-STING can be uncoupled.…”

Lamin B1 sequesters 53BP1 to control its recruitment to DNA damage

“…These data suggest that lamin A overexpression, in contrast to lamin B1 overexpression, does not impede 53BP1 recruitment by a sequestration mechanism, but likely due to defect in 53BP1 transport to nucleus as it has been reported ( 32 ). Different links between lamin A and DNA repair have been established ( 68 ), thus many other consequences of lamin A dysregulation could also account for the persistence of DNA damage ( 68 ). It has been also proposed that lamin A affects foci stability and could interact with γH2AX ( 69 ), the overexpression of lamin A may lead to a prolonged γH2AX signal.…”

Innate immunity mediator STING modulates nascent DNA metabolism at stalled forks in human cells

“…We propose that the INM STING associates with chromatin in the context of lamina/chromatin complexes. This context provides ample opportunities for STING to affect NDD, since lamins and lamin-associated proteins are extensively implicated in the regulation of replication fork metabolism [reviewed in ( Graziano et al, 2018 ; Willaume et al, 2021 )], including but not limited to the recruitment of RPA ( Graziano et al, 2021 ; Bao et al, 2022 ) ( Figure 8C ).…”