PT  - JOURNAL ARTICLE
AU  - Jerome Irianto
AU  - Charlotte R. Pfeifer
AU  - Yuntao Xia
AU  - Avathamsa Athirasala
AU  - Irena L. Ivanovska
AU  - Roger A. Greenberg
AU  - Dennis E. Discher
TI  - Constricted cell migration causes nuclear lamina damage, DNA breaks, and squeeze-out of repair factors
AID  - 10.1101/035626
DP  - 2015 Jan 01
TA  - bioRxiv
PG  - 035626
4099  - http://biorxiv.org/content/early/2015/12/30/035626.short
4100  - http://biorxiv.org/content/early/2015/12/30/035626.full
AB  - Genomic variation across cancers scales with tissue stiffness: meta-analyses show tumors in stiff tissues such as lung and bone exhibit up to 100-fold more variation than tumors in soft tissues such as marrow and brain. Here, nuclear lamina damage and DNA double-strand breaks (DSBs) result from invasive migration of cancer cells through stiff constrictions. DSBs increase with lamin-A knockdown and require micro-pores sufficiently small for lamins to impede migration. Blebs in the vast majority of post-migration nuclei are enriched in lamin-A but deficient in lamin-B and an age-associated form of lamin-A. Validation of DSBs by an electrophoretic comet assay calibrates against a cancer line having nuclease sites engineered in chromosome-1, and DSB-bound repair factors in nuclei pulled into constrictions show folded chromatin orients, extends, and concentrates without fragmentation. Mobile repair proteins simultaneously segregate away from pore-condensed chromatin. Global squeeze-out of repair factors and loss with lamin-A-dependent rupture explains why overexpression of repair factors cannot rescue DSBs in migration through stiff constrictions, ultimately favoring genomic variation.