The DNA damage response (DDR) protects cells against genomic instability. Surprisingly, little is known about the differences in DDR across tissues, which may affect cancer evolutionary trajectories and chemotherapy response. Using mathematical modeling and quantitative experiments, we found that the DDR is regulated differently in human breast and lung primary cells. Equal levels of cisplatin-DNA lesions caused stronger Chk1 activation in lung cells, leading to resistance. In contrast, breast cells were more resistant and showed more Chk2 activation in response to doxorubicin. Further analyses indicate that Chk1 activity played a regulatory role in p53 phosphorylation, whereas Chk2 activity was essential for p53 activation and p21 expression. We propose a novel “friction model,” in which the balance of p53 and p21 levels contributes to the apoptotic response in different tissues. Our results suggest that modulating the balance of p53 and p21 dynamics could optimize the response to chemotherapy.

DNA损伤反应（DDR）保护细胞免受基因组不稳定的影响。令人惊讶的是，关于DDR在不同组织之间的差异知之甚少，这可能会影响癌症的进化轨迹和化学疗法的反应。通过数学建模和定量实验，我们发现DDR在人的乳房和肺原代细胞中受到不同的调节。同等水平的顺铂-DNA损伤会导致肺细胞中更强的Chk1活化，从而导致耐药性。相反，乳腺细胞对阿霉素的反应更具抵抗力，并且显示更多的Chk2激活。进一步的分析表明，Chk1活性在p53磷酸化中起调节作用，而Chk2活性对于p53激活和p21表达必不可少。我们提出了一种新颖的“摩擦模型” 其中p53和p21水平的平衡有助于不同组织的凋亡反应。我们的结果表明，调节p53和p21动态平衡可以优化对化学疗法的反应。