Cancer metastasis is the process by which cells from the primary tumor invade into the surrounding extracellular matrix and neighboring tissue and spread to distant organs in the body through the blood or lymphatic system. This process is responsible for majority of cancer related deaths. During metastasis, cancer cells encounter very tiny interstitial spaces, smaller than the size of the cell’s nucleus. Migration through such confined spaces, puts considerable pressure on the nucleus, which is the largest and stiffest organelle in the cell. The nucleus experiences severe deformations and in some cases, nuclear envelope rupture as well as DNA damage during this migration. Here, we investigated the cause of DNA damage and the impact of DNA damage repair kinases during confined migration. We also examined the role of nuclear envelope protein lamin A/C in promoting confined cancer cell migration in breast cancers. Using cell-lines, live-cell imaging and microfluidic devices that mimic the interstitial spaces found in vivo, we show that DNA damage is caused by two distinct but overlapping events – nuclear deformation and nuclear envelope rupture. The main cause of DNA damage, varies for each cell line. Moreover, nuclear deformation duringconfined migration or due to nuclear compression leads to increased replication stress, possibly due to replication fork stalling. Our findings suggest that nuclear deformation during confined migration, causes DNA damage by increasing replication stress. We also evaluated the role of DNA damage repair kinase ATM in promoting confined migration. Using chemical inhibitors, stable and conditional depletion of ATM, we show that ATM regulates levels of nuclear lamin A protein. Furthermore, lack of ATM makes nuclei more deformable and increases migration speed through confined spaces, similar to those encountered during metastasis. Additionally, we examined the role of A-type lamins in modulating nuclear deformability and promoting breast cancer progression. Our results indicate that more aggressive breast cancers have low lamin A/C expression which correlates to increased nuclear deformability in those cells. Moreover, increasing lamin A levels reduces nuclear deformability and impedes migration through confined spaces in aggressive breast cancer cells. Lamin A levels also modulate cell shape and proliferation rates and are associated with poor disease-free survival in breast cancer patients. Thus we have identified a new role for ATM in modulating nuclear mechanics by regulating lamin levels and established A-type lamins as a potential clinical marker to predict breast cancer patient outcomes. This thesis, thus, provides mechanistic insights into the cause of DNA damage as well as the role of nuclear envelope proteins (like lamins) and DNA damage repair proteins (like ATM) during confined migration.