Self-control denotes the ability to override current desires to render behavior consistent with long-term goals. A key assumption is that self-control is required when short-term desires are ...transiently stronger (more preferred) than long-term goals and people would yield to temptation without exerting self-control. We argue that this widely shared conception of self-control raises a fundamental yet rarely discussed conceptual paradox: How is it possible that a person most strongly desires to perform a behavior (e.g., eat chocolate) and at the same time desires to recruit self-control to prevent themselves from doing it? A detailed analysis reveals that three common assumptions about self-control cannot be true simultaneously. To avoid the paradox, any coherent theory of self-control must abandon either the assumption (a) that recruitment of self-control is an intentional process, or (b) that humans are unitary agents, or (c) that self-control consists in overriding the currently strongest desire. We propose a taxonomy of different kinds of self-control processes that helps organize current theories according to which of these assumptions they abandon. We conclude by outlining unresolved questions and future research perspectives raised by different conceptions of self-control and discuss implications for the question of whether self-control can be considered rational.
Abstract
Inhibition of the kinase ATR, a central regulator of the DNA damage response, eliminates subsets of cancer cells in certain tumors. As previously shown, this is at least partly attributable ...to synthetic lethal interactions between
ATR
and
POLD1
, the catalytic subunit of the polymerase δ. Various
POLD1
variants have been found in colorectal cancer, but their significance as therapeutic targets for ATR pathway inhibition remains unknown. Using CRISPR/Cas9 in the colorectal cancer cell line DLD-1, which harbors four
POLD1
variants, we established heterozygous
POLD1
-knockout clones with exclusive expression of distinct variants to determine the functional relevance of these variants individually by assessing their impact on ATR pathway activation, DNA replication, and cellular sensitivity to inhibition of ATR or its effector kinase CHK1. Of the four variants analyzed, only POLD1
R689W
affected POLD1 function, as demonstrated by compensatory ATR pathway activation and impaired DNA replication. Upon treatment with ATR or CHK1 inhibitors, POLD1
R689W
strongly decreased cell survival in vitro, which was attributable at least partly to S phase impairment and apoptosis. Similarly, treatment with the ATR inhibitor AZD6738 inhibited growth of murine xenograft tumors, harboring the POLD1
R689W
variant, in vivo. Our
POLD1
-knockout model thus complements algorithm-based models to predict the pathogenicity of tumor-specific variants of unknown significance and illustrates a novel and potentially clinically relevant therapeutic approach using ATR/CHK1 inhibitors in
POLD1
-deficient tumors.
Inhibition of the kinase ATR, a central regulator of the DNA damage response, eliminates subsets of cancer cells in certain tumors. As previously shown, this is at least partly attributable to ...synthetic lethal interactions between ATR and POLD1, the catalytic subunit of the polymerase δ. Various POLD1 variants have been found in colorectal cancer, but their significance as therapeutic targets for ATR pathway inhibition remains unknown. Using CRISPR/Cas9 in the colorectal cancer cell line DLD-1, which harbors four POLD1 variants, we established heterozygous POLD1-knockout clones with exclusive expression of distinct variants to determine the functional relevance of these variants individually by assessing their impact on ATR pathway activation, DNA replication, and cellular sensitivity to inhibition of ATR or its effector kinase CHK1. Of the four variants analyzed, only POLD1
affected POLD1 function, as demonstrated by compensatory ATR pathway activation and impaired DNA replication. Upon treatment with ATR or CHK1 inhibitors, POLD1
strongly decreased cell survival in vitro, which was attributable at least partly to S phase impairment and apoptosis. Similarly, treatment with the ATR inhibitor AZD6738 inhibited growth of murine xenograft tumors, harboring the POLD1
variant, in vivo. Our POLD1-knockout model thus complements algorithm-based models to predict the pathogenicity of tumor-specific variants of unknown significance and illustrates a novel and potentially clinically relevant therapeutic approach using ATR/CHK1 inhibitors in POLD1-deficient tumors.
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