Abstract
AbstractCockayne syndrome (CS) is an autosomal recessive premature ageing condition mainly characterized by microcephaly, growth failure, and neurodegeneration. It is caused by mutations inERCC6orERCC8genes which encode for Cockayne Syndrome B (CSB) and Cockayne Syndrome A (CSA) proteins, respectively. CSA and CSB have well-characterised roles in transcription-coupled nucleotide excision repair (TC-NER), responsible for the removal of bulky DNA lesions, including those caused by UV irradiation. Here, we report that CSA knockout cells and CSA patient cells (CS-A) carrying a loss-of-function mutation in theERCC8gene exhibit defects in nuclear envelope (NE) integrity. NE dysfunction is a characteristic phenotype of cells from progeroid disorders caused by mutation in NE proteins, such as Hutchinson-Gilford Progeria Syndrome (HGPS). However, it has never been reported in Cockayne Syndrome. We observed that CS-A cells displayed reduced levels of LAP2-emerin-MAN1 (LEM)-domain 2 (LEMD2) at the NE resulting in decreased formation of LEMD2-lamin A/C complexes. In addition, loss of CSA function caused increased actin stress fibers that contributed to enhanced mechanical stress to the NE. Altogether, these led to NE blebbing and ruptures in interphase, causing activation of the innate/immune cGAS/STING signaling pathway. Disrupting the linker of the nucleoskeleton and cytoskeleton (LINC) complex that is responsible for anchoring the cytoskeleton to the NE, rescued the NE phenotypes and reduced the activation of cGAS/STING pathway. This work has revealed a previously uncharacterized role for CSA in regulating NE integrity and shed light on mechanisms that may further explain some of the clinical phenotypes observed in CS patients such as neuroinflammation. This is to our knowledge, the first study showing NE dysfunction in a progeroid syndrome caused by mutations in a DNA damage repair protein, reinforcing the connection between NE deregulation and ageing.
Publisher
Cold Spring Harbor Laboratory