ATR is essential for preservation of cell mechanics and nuclear integrity during interstitial migration

Abstract

ATR responds to mechanical stress at the nuclear envelope and mediates envelope-associated repair of aberrant topological DNA states. By combining microscopy, electron microscopic analysis, biophysical and in vivo models, we report that ATR-defective cells exhibit altered nuclear plasticity and YAP delocalization. When subjected to mechanical stress or undergoing interstitial migration, ATR-defective nuclei collapse accumulating nuclear envelope ruptures and perinuclear cGAS, which indicate loss of nuclear envelope integrity, and aberrant perinuclear chromatin status. ATR-defective cells also are defective in neuronal migration during development and in metastatic dissemination from circulating tumor cells. Our findings indicate that ATR ensures mechanical coupling of the cytoskeleton to the nuclear envelope and accompanying regulation of envelope-chromosome association. Thus the repertoire of ATR-regulated biological processes extends well beyond its canonical role in triggering biochemical implementation of the DNA damage response.

Self-DNA Sensing by cGAS-STING and TLR9 in Autoimmunity: Is the Cytoskeleton in Control?

“…It is thus reasonable to expect an interplay between perturbed actin dynamics, genomic stability, and cGAS activation. In this direction, uncoupling the cytoskeleton from the nuclear envelope in ATR deficient cells was recently shown to cause accumulation of perinuclear cGAS in conditions of mechanical stress ( 62 , 89 , 90 ). The ESCRT machinery involved in endosomal sealing is also recruited at sites of the damaged nuclear envelope for repair ( 91 , 92 ).…”

Regulation of Nuclear Mechanics and the Impact on DNA Damage

“…Interestingly, a recent report also revealed a role for the ATR kinase in nuclear mechanics. Kidiyoor et al showed that ATR ensures coupling of the nuclear envelope to the cytoskeleton, and its depletion leads to changes in chromatin organisation, nuclear softening and reduction in nuclear circularity [ 152 ].…”

Nuclear envelope integrity, DNA replication, damage repair and genome stability

“…Close associations between NE rupture and the loss of lamin A/C and lamin B1 as well as the mutation of nuclear lamins exist in HGPS and cancer (Earle et al, 2020;Penfield et al, 2018). Cancer cells suffer more NE rupture, DNA damage and nuclear deformation through confining space (Denais et al, 2016;Kidiyoor et al, 2020;Shah et al, 2021). The confined migration and compression force increased replication stress and promoted replication fork stalling (Shah et al, 2021).…”

“…The confined migration and compression force increased replication stress and promoted replication fork stalling (Shah et al, 2021). In addition, the ATR defective cells generated NE rupture, perinuclear cGAS (cyclic GMP-AMP synthase) accumulation and aberrant perinuclear chromatin status during interstitial migration or mechanical force loading (Kidiyoor et al, 2020). Loss of NE integrity under mechanical stress also promoted senescence and invasive phenotype by increasing collagen degradation, activation of the ATM kinase and DNA damage.…”