Methods to stabilize mammalian cells

The invention provides gene targets whose restoration leads to genome stabilization in host cells, such as Chinese Hamster Ovary (CHO) cells. Many DNA repair genes are mutated in CHO cells which compromises their ability to repair naturally occurring DNA damage, in particular double-strand breaks (DSBs). Unrepaired DSBs can give rise to chromosomal instability which, in turn, can lead to loss of transgenes from the genome. As a consequence, protein titer can drop significantly, rendering protein production unprofitable. The invention provides a set of mutated DNA repair genes whose restoration yields significant improvement in DSB repair, genome stability, and protein titer.