InterLINCing Chromatin Organization and Mechanobiology in Laminopathies

Shah, Parisha P.; Santini, Garrett T.; Shen, Karen; Jain, Rajan

doi:10.1007/s11886-023-01853-2

Cited by 4 publications

(1 citation statement)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similarly, SUN1 depletion led to the improvement of NE phenotypes in CS-A cells, reinforcing the idea that the forces exerted by actin on the nucleus of CS-A cells contribute to the NE abnormalities and ruptures in these cells. This data also suggests that LINC complex disruption could be an effective strategy to restore cellular homeostasis in multiple syndromes associated with NE dysfunction, and it is an approach that is currently being investigated by other teams (60,61).…”

Section: Discussionmentioning

confidence: 83%

A Novel Role for CSA in the Regulation of Nuclear Envelope Integrity: Uncovering a Non-Canonical Function

Yang,

Lai,

Davies

et al. 2023

Preprint

View full text Add to dashboard Cite

Cockayne 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.

show abstract

Section: Discussionmentioning

confidence: 83%

A Novel Role for CSA in the Regulation of Nuclear Envelope Integrity: Uncovering a Non-Canonical Function

Yang,

Lai,

Davies

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

Microscopy methods to visualize nuclear organization in biomechanical studies

Kim,

Lakadamyali

2024

Current Opinion in Biomedical Engineering

View full text Add to dashboard Cite

A novel role for CSA in the regulation of nuclear envelope integrity: uncovering a non-canonical function

Yang,

Lai,

Davies

et al. 2024

Life Sci. Alliance

View full text Add to dashboard Cite

Cockayne syndrome (CS) is a premature ageing condition characterized by microcephaly, growth failure, and neurodegeneration. It is caused by mutations inERCC6orERCC8encoding for Cockayne syndrome B (CSB) and A (CSA) proteins, respectively. CSA and CSB have well-characterized roles in transcription-coupled nucleotide excision repair, responsible for removing bulky DNA lesions, including those caused by UV irradiation. Here, we report that CSA dysfunction causes defects in the nuclear envelope (NE) integrity. NE dysfunction is characteristic of progeroid disorders caused by a mutation in NE proteins, such as Hutchinson–Gilford progeria syndrome. However, it has never been reported in Cockayne syndrome. We observed CSA dysfunction affected LEMD2 incorporation at the NE and increased actin stress fibers that contributed to enhanced mechanical stress to the NE. Altogether, these led to NE abnormalities associated with the activation of the cGAS/STING pathway. Targeting the linker of the nucleoskeleton and cytoskeleton complex was sufficient to rescue these phenotypes. This work reveals NE dysfunction in a progeroid syndrome caused by mutations in a DNA damage repair protein, reinforcing the connection between NE deregulation and ageing.

show abstract

InterLINCing Chromatin Organization and Mechanobiology in Laminopathies

Cited by 4 publications

References 67 publications

A Novel Role for CSA in the Regulation of Nuclear Envelope Integrity: Uncovering a Non-Canonical Function

A Novel Role for CSA in the Regulation of Nuclear Envelope Integrity: Uncovering a Non-Canonical Function

Microscopy methods to visualize nuclear organization in biomechanical studies

A novel role for CSA in the regulation of nuclear envelope integrity: uncovering a non-canonical function

Contact Info

Product

Resources

About