Transcription factors are active in every phase of the cell cycle, but different transcription factors switch on and off at different times. There is no single phase where all transcription factors turn on together. Instead, they operate in coordinated waves: some activate genes during G1, others during S phase, others during G2, and a smaller group even remains active during mitosis. The one phase where transcription factor activity drops dramatically as a whole is M phase (mitosis), when the cell is physically dividing.
How Transcription Factors Cycle Through Each Phase
The cell cycle has four main phases: G1 (growth and preparation), S (DNA replication), G2 (preparation for division), and M (mitosis, or actual division). At each transition, specific transcription factors activate a new set of genes the cell needs for the next step. Think of it as a relay race: one group of transcription factors hands off to the next as the cell progresses.
In yeast, which scientists use as a model because the system is well-characterized, this relay is especially clear. The transcription factors SBF and MBF activate genes for DNA replication and cell growth during the G1/S transition. They then pass a signal to a factor called Hcm1, which turns on genes needed for chromosome handling during S phase. During G2 and into mitosis, a complex called SFF activates genes involved in the mechanics of cell division. Finally, as the cell exits mitosis and re-enters G1, factors like Ace2 and Swi5 activate genes that help daughter cells transition into the next cycle.
Human cells follow a similar logic. The E2F family of transcription factors is one of the best-studied examples. E2F-4 is active in the nucleus during G0 (quiescence) and early G1, where it helps repress genes the cell doesn’t need yet. As the cell commits to dividing, E2F-1 takes over in late G1 and S phase, switching on genes required for DNA replication. E2F-1 is then shut down during late S phase when an enzyme tags it for inactivation. This hand-off ensures the right genes fire at the right time.
G2 Phase: Preparing for Division
G2 is sometimes overlooked, but it has its own dedicated transcription factors. The most prominent is FoxM1, a transcription factor that controls genes the cell needs to enter mitosis successfully. FoxM1 is actually present earlier in the cell cycle but is kept inactive by a built-in self-repressing region in the protein. During G2, enzymes associated with cyclin A physically modify FoxM1, releasing that internal brake and allowing it to activate its target genes. This ensures the cell doesn’t prematurely express mitosis-related genes during S phase.
Why Transcription Largely Shuts Down During Mitosis
Mitosis is the one phase where global transcription factor activity drops sharply. This has been observed for over 60 years, and several mechanisms explain it.
First, the nuclear envelope breaks apart. Since transcription factors are normally concentrated inside the nucleus, this breakdown suddenly dilutes them into the much larger volume of the whole cell, reducing their effective concentration at any given spot on the DNA. Second, chromosomes condense into tightly packed structures that are physically harder for transcription factors to access. Third, the cell adds chemical tags (phosphate groups) to many transcription factors specifically during mitosis. For example, the stem cell factor Oct4 gets phosphorylated by an enzyme called Aurora kinase B during mitosis, which directly blocks it from binding its target genes. Similar phosphorylation events disable many other transcription factors at this stage.
The combined effect is a massive, coordinated silencing of gene expression right when the cell needs to focus all its machinery on physically separating its chromosomes.
The Exceptions: Mitotic Bookmarking
Despite the general shutdown, the old idea that transcription stops completely during mitosis has been revised. Sensitive methods for measuring newly made RNA have revealed low levels of transcription still running along mitotic chromosomes. Hundreds of specific transcripts actually increase during mitosis, and active transcription occurs at centromeres (the chromosome regions essential for proper separation).
Some transcription factors stay physically attached to condensed chromosomes during mitosis, a phenomenon called mitotic bookmarking. These “bookmarking” factors include GATA1 (important in blood cell development), FoxA1 (involved in liver and breast tissue), Runx2 (critical for bone formation), and several others. The idea is that by remaining on the DNA, these factors mark key genes so daughter cells can rapidly reactivate them once division is complete, preserving cell identity. GATA1 illustrates the nuance well: microscopy initially suggested it completely left chromosomes during mitosis, but more sensitive genome-wide techniques revealed it actually stays partially bound.
How Transcription Restarts After Division
Once the cell exits mitosis, transcription factors don’t all flood back simultaneously. Computational analysis of single-cell data has identified distinct waves of reactivation. Roughly 19% of transcription factors show positive activity during mitosis itself, peaking in the first minutes and then declining. Another 36% are repressed during mitosis but become highly active in early G1, forming a second wave. The remaining factors maintain relatively steady activity regardless of phase.
The median lag time for transcription to restart after mitotic exit is about 30 minutes, with the full transition from the start of mitosis to interphase taking roughly 67 minutes on average. This rapid, ordered reactivation is what allows daughter cells to quickly resume normal gene expression and begin growing.
Why Phase-Specific Activity Matters in Cancer
Cancer cells often hijack phase-specific transcription factors to drive uncontrolled growth. Many cancer therapies work by disrupting transcription factor activity at particular points in the cell cycle. One well-established example targets the fusion protein PML-RARα, which is produced by a chromosome rearrangement in acute promyelocytic leukemia. The drug all-trans retinoic acid binds directly to this abnormal transcription factor, triggers its destruction, and restores normal gene regulation, allowing leukemia cells to mature and stop dividing. Other approaches target the enzymes that activate transcription factors indirectly, such as drugs that block specific cell-cycle-dependent kinases or histone-modifying enzymes that transcription factors rely on to access DNA.
The phase-specific nature of transcription factor activity is what makes these strategies possible. Because different factors dominate at different points in the cycle, therapies can be designed to hit cancer cells precisely when they depend on a particular transcription factor to keep dividing.