RCC1 depletion drives protein transport defects and rupture in micronuclei

Area of Science:

• Cell Biology
• Genetics
• Cancer Research

Background:

• Micronuclei (MN) are key indicators of chromosome instability.
• MN rupture leads to genome instability, metastasis, and immune response.
• The causes of nuclear envelope (NE) defects in MN remain unclear.

Purpose of the Study:

• Investigate the mechanisms underlying MN rupture and NE defects.
• Determine the role of histone methylation and protein transport in MN stability.
• Correlate MN rupture timing with cancer mutational signatures.

Main Methods:

• Analysis of histone methylation in small MN.
• Assessment of protein export and import defects in MN.
• Examination of RCC1 levels in MN.
• Analysis of the Pan-Cancer Analysis of Whole Genomes (PCAWG) dataset for mutational signatures.

Main Results:

• Histone methylation promotes rupture and NE defects in small MN.
• All MN exhibit constitutive nuclear export defects, driving growth and NE gaps.
• Decreased RCC1 levels cause export defects; further loss in euchromatic MN causes import defects, suppressing rupture.
• Analysis of PCAWG data reveals APOBEC and DNA polymerase E signatures linked to early and mid-rupturing chromosomes in chromothripsis.

Conclusions:

• A novel model of MN rupture is proposed, driven by protein export defects and subsequent NE gaps.
• MN growth and rupture susceptibility are influenced by protein transport dynamics.
• MN rupture timing may dictate the patterns of structural variation in chromothripsis, with implications for cancer development.