Abstract
The DNA double-strand break (DSB) is the most cytotoxic lesion and compromises genome stability. In an attempt to efficiently repair DSBs, cells activate ATM kinase, which orchestrates the DNA damage response (DDR) by activating cell cycle checkpoints and initiating DSB repair pathways. In physiological B cell development, however, programmed DSBs are generated as intermediates for effective immune responses and the maintenance of genomic integrity. Disturbances of these pathways are at the heart of B cell lymphomagenesis. Here, we review the role of DNA repair and cell cycle control on B cell development and lymphomagenesis. In addition, we highlight the intricate relationship between the DDR and the tumor microenvironment (TME). Lastly, we provide a clinical perspective by highlighting treatment possibilities of defective DDR signaling and the TME in mantle cell lymphoma, which serves as a blueprint for B cell lymphomas.
Highlights
DNA damage activates a complex signaling network, commonly referred to as the DNA damage response (DDR) [1]
In B cell development, where cell division is more tightly controlled in order to prevent aberrant genetic alterations, mutations in proliferation genes have a much greater impact, making lymphomas the ideal candidate for cell cycle inhibitor therapies
Further investigation showed that CDK4/6 inhibition has the ability to shift the DDR response from homologous recombination repair (HR) to classical non-homologous end joining (cNHEJ) [57], in addition to reducing PARP1 expression levels [58], making it a potential candidate to use alongside DNA
Summary
DNA damage activates a complex signaling network, commonly referred to as the DNA damage response (DDR) [1]. The DDR induces cell cycle checkpoints and allows time for DNA repair, or—if the lesions are beyond repair capacity—leads to the activation of cell death pathways [1]. These checkpoints are the G1/S checkpoint, the S phase checkpoint, and the G2/M checkpoint. Upon DNA damage, activation of the checkpoint kinase 1 (CHK1) by the DDR results in the activation of WEE1, halting the cell cycle and either allowing repair or inducing apoptosis [10]. The fundamental process of B cell development is crucially dependent on functional DNA repair and cell cycle control mechanisms and deficiencies within these pathways do promote lymphomagenesis but are frequently found in B cell lymphomas [14]. DDR deficiency and leveraging the increasingly understood TME features using MCL as a blueprint for B cell lymphomas
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