Efficient terminal erythroid differentiation requires the APC/C cofactor Cdh1 to limit replicative stress in erythroblasts.

Myriam Cuadrado, Javier Garzón, Sergio Moreno, Irene García-Higuera

Scientific reports 2022 Jun 21

filter terms:

The APC/C-Cdh1 ubiquitin ligase complex drives proteosomal degradation of cell cycle regulators and other cellular proteins during the G1 phase of the cycle. The complex serves as an important modulator of the G1/S transition and prevents premature entry into S phase, genomic instability, and tumor development. Additionally, mounting evidence supports a role for this complex in cell differentiation, but its relevance in erythropoiesis has not been addressed so far. Here we show, using mouse models of Cdh1 deletion, that APC/C-Cdh1 activity is required for efficient terminal erythroid differentiation during fetal development as well as postnatally. Consistently, Cdh1 ablation leads to mild but persistent anemia from birth to adulthood. Interestingly, loss of Cdh1 seems to affect both, steady-state and stress erythropoiesis. Detailed analysis of Cdh1-deficient erythroid populations revealed accumulation of DNA damage in maturing erythroblasts and signs of delayed G2/M transition. Moreover, through direct assessment of replication dynamics in fetal liver cells, we uncovered slow fork movement and increased origin usage in the absence of Cdh1, strongly suggesting replicative stress to be the underlying cause of DNA lesions and cell cycle delays in erythroblasts devoid of Cdh1. In turn, these alterations would restrain full maturation of erythroblasts into reticulocytes and reduce the output of functional erythrocytes, leading to anemia. Our results further highlight the relevance of APC/C-Cdh1 activity for terminal differentiation and underscore the need for precise control of replication dynamics for efficient supply of red blood cells. © 2022. The Author(s).

Citation

Myriam Cuadrado, Javier Garzón, Sergio Moreno, Irene García-Higuera. Efficient terminal erythroid differentiation requires the APC/C cofactor Cdh1 to limit replicative stress in erythroblasts. Scientific reports. 2022 Jun 21;12(1):10489