Mind the replication gap.

Area of Science:

• Cell Biology
• Genetics
• Molecular Biology

Background:

• Mammalian cells require DNA replication completion before chromosome segregation for genome integrity.
• Cells possess pathways to repair stalled replication forks and delay cell cycle progression.
• Mild replication stress can cause cells to enter mitosis with incompletely replicated DNA.

Purpose of the Study:

• To review cellular responses to under-replicated DNA structures that bypass S/G2 surveillance.
• To discuss the mitotic break-induced replication pathway (MBIR) for finishing DNA synthesis during mitosis.
• To explore how replication stress contributes to chromosome instability and cancer genome evolution.

Main Methods:

• Literature review of cellular responses to replication stress.
• Focus on the mitotic break-induced replication pathway (MBIR).
• Discussion of recent data on replication stress, chromosome instability, and cancer.

Main Results:

• Under-replicated DNA, particularly at fragile sites, forms branched structures that threaten chromosome segregation.
• The mitotic break-induced replication pathway (MBIR) is proposed to resolve these structures during prophase.
• Mild replication stress can lead to chromosome instability and mutations, promoting cancer genome evolution.

Conclusions:

• Cells have mechanisms to manage under-replicated DNA, but these can be overwhelmed by mild replication stress.
• The MBIR pathway offers a potential mechanism for completing DNA synthesis in mitosis.
• Replication stress is a significant factor in driving chromosome instability and cancer development.